Cadmium (T3D0007)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (27)XML
Targets (27)
Record Information
Version2.0
Creation Date2009-03-06 18:57:54 UTC
Update Date2014-12-24 20:20:51 UTC
Accession NumberT3D0007
Identification
Common NameCadmium
ClassSmall Molecule
DescriptionCadmium (group IIB of the periodic table of elements) is a heavy metal. It is not a naturally occurring metal in biological systems. Cadmium poses severe risks to human health. Physiologically, it exists as an ion in the body. Up to this day, it has not been shown that cadmium has any physiological function within the human body. Interest has therefore risen in its biohazardous potential. As first described by Friedrich Stromeyer (Gottingen, Germany) in 1817, cadmium intoxication can lead to kidney, bone, and pulmonary damage. Cadmium is widely used in industrial processes, e.g as an anticorrosive agent, as a stabilizer in PVC products, as a colour pigment, a neutron absorber in nuclear power plants, and in the fabrication of nickel cadmium batteries. Phosphate fertilizers also show a big cadmium load. Although some cadmium containing products can be recycled, a large share of the general cadmium pollution is caused by dumping and incinerating cadmium polluted waste. In Scandinavia for example, cadmium concentration in agricultural soil increases by 0.2 percent per year. Total global emission of cadmium amounts to 7000 t/year. The maximum permissible value for workers according to German law is 15 ug/l. For comparison: Non-smokers show an average cadmium blood concentration of 0.5 ug/l. Basically there are three possible ways of cadmium resorption: Gastrointestinal, pulmonary and dermal. The uptake through the human gastrointestinal is approximately 5 percent of an ingested amount of cadmium, depending on the exact dose and nutritional composition. The major source of inhalative cadmium intoxication is cigarette smoke. The human lung resorbes 40 to 60 percent of the cadmium in tobacco smoke. Little research has been done on dermal absorption of cadmium. Two mechanisms facilitate cadmium absorption by the skin: binding of a free cadmium ion to sulfhydryl radicals of cysteine in epidermal keratins, or an induction and complexing with metallothionein. Once taken up by the blood, the majority of cadmium is transported bound to proteins, such as Albumin and Metallothionein. The first organ reached after cadmium uptake into the GI-blood is the liver. Here cadmium induces the production of Metallothionein. After consecutive hepatocyte necrosis and apoptosis, Cd-Metallothionein complexes are washed into sinusoidal blood. From here, parts of the absorbed cadmium enter the entero-hepatical cycle via secretion into the biliary tract in form of Cadmium-glutathione conjugates. Enzymatically degraded to cadmium-cysteine complexes in the biliary tree, cadmium reenters the small intestines. The main organ for long-term cadmium accumulation is the kidney. Here the half life period for cadmium is approximately 10 years. A life long intake can therefore lead to a cadmium accumulation in the kidney, consequently resulting in tubulus cell necrosis. The blood concentration of cadmium serves as a reliable indicator for a recent exposition, while the urinary concentration reflects past exposure, body burden and renal accumulation. Excretion of Cadmium takes place via faeces and urine. (5).
Compound Type
  • Cadmium Compound
  • Cigarette Toxin
  • Food Toxin
  • Household Toxin
  • Industrial/Workplace Toxin
  • Inorganic Compound
  • Metabolite
  • Metal
  • Natural Compound
  • Pollutant
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
Cadmium ion
Cadmium(2+)
Cadmium(2+) ion
Cadmium(II)
Cadmium(II) cation
Cadmium(II) ion
Cd(2+)
Cd2+
Metallic cadmium
Chemical FormulaCd
Average Molecular Mass112.410 g/mol
Monoisotopic Mass113.902 g/mol
CAS Registry Number7440-43-9
IUPAC Namecadmium(2+) ion
Traditional Namecadmium(2+) ion
SMILES[Cd++]
InChI IdentifierInChI=1S/Cd/q+2
InChI KeyInChIKey=WLZRMCYVCSSEQC-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of inorganic compounds known as homogeneous transition metal compounds. These are inorganic compounds containing only metal atoms,with the largest atom being a transition metal atom.
KingdomInorganic compounds
Super ClassHomogeneous metal compounds
ClassHomogeneous transition metal compounds
Sub ClassNot Available
Direct ParentHomogeneous transition metal compounds
Alternative ParentsNot Available
Substituents
  • Homogeneous transition metal
Molecular FrameworkNot Available
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceBluish-white metallic solid.
Experimental Properties
PropertyValue
Melting Point321°C
Boiling Point1040 K (767 °C, 1413 °F)
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
logP-0.07ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity0 m³·mol⁻¹ChemAxon
Polarizability1.78 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03di-0900000000-f8713a66369086ec0ad52016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03di-0900000000-f8713a66369086ec0ad52016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03di-0900000000-f8713a66369086ec0ad52016-06-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0900000000-c6c3e3d7e513c880c7f42016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03di-0900000000-c6c3e3d7e513c880c7f42016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03di-0900000000-c6c3e3d7e513c880c7f42016-08-03View Spectrum
Toxicity Profile
Route of ExposureOral (7) ; inhalation (7) ; dermal (7)
Mechanism of ToxicityCadmium initially binds to metallothionein and is transported to the kidney. Toxic effects are observed once the concentration of cadmium exceeds that of available metallothionein, and it has also been shown that the cadmium-metallothionein complex may be damaging. Accumulation of cadmium in the kidney results in increased excretion of vital low and high molecular weight proteins. Cadmium is a high affinity zinc analog and can interfere in its biological processes. It also binds to and activates the estrogen receptor, likely stimulating the growth of certain types of cancer cells and causing other estrogenic effects, such as reproductive dysfunction. Cadmium causes cell apoptosis by activating mitogen-activated protein kinases. (8, 1, 2, 3)
MetabolismCadmium is absorbed from oral, inhalation, and dermal routes. Cadmium initially binds to metallothionein and albumin and is transported mainly to the kidney and liver. Toxic effects are observed once the concentration of cadmium exceeds that of available metallothionein, and it has also been shown that the cadmium-metallothionein complex may be damaging. Cadmium is not known to undergo any direct metabolic conversion and is excreted unchanged, mainly in the urine. (7)
Toxicity ValuesLD50: 225 mg/kg (Oral, Rat) (6) LD50: 5700 ug/kg (Intraperitoneal, Mouse) (6)
Lethal Dose150 mg (oral) or 39 mg/m3 over 20 minutes (inhalation) for an adult human. (6, 4)
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (11)
Uses/SourcesCadmium is used mainly in the electroplating of other metals and the production of metal alloys. It can be found in batteries, pigments, metal coatings, and plastics. Exposure usually occurs in an industrial setting, but can also result from breathing cigarette smoke and eating contaminated foods. (7)
Minimum Risk LevelAcute Inhalation: 0.00003 mg/m3 (10) Chronic Inhalation: 0.00001 mg/m3 (10) Intermediate Oral: 0.0005 mg/kg/day (10) Chronic Oral: 0.0001 mg/kg/day (10)
Health EffectsChronic exposure to cadmium fumes can cause chemical pneumonitis, pulmonary edema, and lung diseases such as bronchitis and emphysema. Cadmium also accumulates in the kidneys, causing permanent damage. Loss of bone density also occurs. (7)
SymptomsAcute inhalation of cadmium fumes results in metal fume fever, which is characterized by chills, fever, headache, weakness, dryness of the nose and throat, chest pain, and coughing. Ingestion of cadmium causes vomiting and diarrhea. (7)
TreatmentCadmium poisoning is treated by removal from exposure and supportive care. If ingested, induced vomiting or gastric lavage may be performed. (12)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDHMDB03638
PubChem Compound ID31193
ChEMBL IDNot Available
ChemSpider ID28935
KEGG IDC01413
UniProt IDNot Available
OMIM ID
ChEBI ID48775
BioCyc IDCD%2b2
CTD IDD002104
Stitch IDCadmium
PDB IDCD
ACToR ID6393
Wikipedia LinkCadmium
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Tsuruoka S, Swenson ER, Fujimura A, Imai M: Mechanism of Cd-induced inhibition of Na-glucose cotransporter in rabbit proximal tubule cells: roles of luminal pH and membrane-bound carbonic anhydrase. Nephron Physiol. 2008;110(2):p11-20. doi: 10.1159/000161986. Epub 2008 Oct 13. [18849623 ]
  2. Zang Y, Odwin-Dacosta S, Yager JD: Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells. Toxicol Lett. 2009 Jan 30;184(2):134-8. doi: 10.1016/j.toxlet.2008.10.032. Epub 2008 Nov 11. [19041697 ]
  3. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
  4. Buckler HM, Smith WD, Rees WD: Self poisoning with oral cadmium chloride. Br Med J (Clin Res Ed). 1986 Jun 14;292(6535):1559-60. [3087515 ]
  5. Godt J, Scheidig F, Grosse-Siestrup C, Esche V, Brandenburg P, Reich A, Groneberg DA: The toxicity of cadmium and resulting hazards for human health. J Occup Med Toxicol. 2006 Sep 10;1:22. [16961932 ]
  6. Lewis RJ (1996). Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold.
  7. ATSDR - Agency for Toxic Substances and Disease Registry (2008). Toxicological profile for cadmium. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
  8. OSHA (2005). Safety and Health Topics: Cadmium. Occupational Safety & Health Administrations. [Link]
  9. Wikipedia. Metallothionein. Last Updated 20 December 2008. [Link]
  10. ATSDR - Agency for Toxic Substances and Disease Registry (2001). Minimal Risk Levels (MRLs) for Hazardous Substances. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
  11. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
  12. International Programme on Chemical Safety (IPCS) INCHEM (1992). Poison Information Monograph for Cadmium. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Metallothionein-3
General Function:
Zinc ion binding
Specific Function:
Binds heavy metals. Contains three zinc and three copper atoms per polypeptide chain and only a negligible amount of cadmium. Inhibits survival and neurite formation of cortical neurons in vitro.
Gene Name:
MT3
Uniprot ID:
P25713
Molecular Weight:
6926.855 Da
References
  1. Hasler DW, Jensen LT, Zerbe O, Winge DR, Vasak M: Effect of the two conserved prolines of human growth inhibitory factor (metallothionein-3) on its biological activity and structure fluctuation: comparison with a mutant protein. Biochemistry. 2000 Nov 28;39(47):14567-75. [11087412 ]
  2. Palumaa P, Eriste E, Njunkova O, Pokras L, Jornvall H, Sillard R: Brain-specific metallothionein-3 has higher metal-binding capacity than ubiquitous metallothioneins and binds metals noncooperatively. Biochemistry. 2002 May 14;41(19):6158-63. [11994011 ]
  3. Palumaa P, Njunkova O, Pokras L, Eriste E, Jornvall H, Sillard R: Evidence for non-isostructural replacement of Zn(2+) with Cd(2+) in the beta-domain of brain-specific metallothionein-3. FEBS Lett. 2002 Sep 11;527(1-3):76-80. [12220637 ]
  4. Zheng WJ, Wu F, Zhuang HQ, Lu C, Yang F, Ma WL, Hua ZC: Expression of human metallothionein III and its metalloabsorption capability in Escherichia coli. Prep Biochem Biotechnol. 2004 Aug;34(3):265-78. [15461142 ]
  5. Palumaa P, Tammiste I, Kruusel K, Kangur L, Jornvall H, Sillard R: Metal binding of metallothionein-3 versus metallothionein-2: lower affinity and higher plasticity. Biochim Biophys Acta. 2005 Mar 14;1747(2):205-11. Epub 2004 Dec 19. [15698955 ]
  6. Toriumi S, Saito T, Hosokawa T, Takahashi Y, Numata T, Kurasaki M: Metal binding ability of metallothionein-3 expressed in Escherichia coli. Basic Clin Pharmacol Toxicol. 2005 Apr;96(4):295-301. [15755312 ]
  7. Kameo S, Nakai K, Kurokawa N, Kanehisa T, Naganuma A, Satoh H: Metal components analysis of metallothionein-III in the brain sections of metallothionein-I and metallothionein-II null mice exposed to mercury vapor with HPLC/ICP-MS. Anal Bioanal Chem. 2005 Apr;381(8):1514-9. Epub 2005 Mar 22. [15782327 ]
Target Details
2. DNA repair protein complementing XP-A cells
General Function:
Protein homodimerization activity
Specific Function:
Involved in DNA excision repair. Initiates repair by binding to damaged sites with various affinities, depending on the photoproduct and the transcriptional state of the region. Required for UV-induced CHEK1 phosphorylation and the recruitment of CEP164 to cyclobutane pyrimidine dimmers (CPD), sites of DNA damage after UV irradiation.
Gene Name:
XPA
Uniprot ID:
P23025
Molecular Weight:
31367.71 Da
References
  1. Buchko GW, Hess NJ, Kennedy MA: Cadmium mutagenicity and human nucleotide excision repair protein XPA: CD, EXAFS and (1)H/(15)N-NMR spectroscopic studies on the zinc(II)- and cadmium(II)-associated minimal DNA-binding domain (M98-F219). Carcinogenesis. 2000 May;21(5):1051-7. [10783332 ]
  2. Mustra DJ, Warren AJ, Wilcox DE, Hamilton JW: Preferential binding of human XPA to the mitomycin C-DNA interstrand crosslink and modulation by arsenic and cadmium. Chem Biol Interact. 2007 Jun 30;168(2):159-68. Epub 2007 Apr 19. [17512921 ]
Target Details
3. Amyloid beta A4 protein
General Function:
Transition metal ion binding
Specific Function:
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts.Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).
Gene Name:
APP
Uniprot ID:
P05067
Molecular Weight:
86942.715 Da
References
  1. Syme CD, Viles JH: Solution 1H NMR investigation of Zn2+ and Cd2+ binding to amyloid-beta peptide (Abeta) of Alzheimer's disease. Biochim Biophys Acta. 2006 Feb;1764(2):246-56. Epub 2005 Oct 14. [16266835 ]
Target Details
4. C-Jun-amino-terminal kinase-interacting protein 1
General Function:
Protein kinase inhibitor activity
Specific Function:
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
Gene Name:
MAPK8IP1
Uniprot ID:
Q9UQF2
Molecular Weight:
77523.56 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
5. C-Jun-amino-terminal kinase-interacting protein 2
General Function:
Structural molecule activity
Specific Function:
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. JIP2 inhibits IL1 beta-induced apoptosis in insulin-secreting cells. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity).
Gene Name:
MAPK8IP2
Uniprot ID:
Q13387
Molecular Weight:
87973.915 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
6. C-Jun-amino-terminal kinase-interacting protein 3
General Function:
Receptor signaling complex scaffold activity
Specific Function:
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity).
Gene Name:
MAPK8IP3
Uniprot ID:
Q9UPT6
Molecular Weight:
147455.935 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
7. C-Jun-amino-terminal kinase-interacting protein 4
General Function:
Receptor signaling complex scaffold activity
Specific Function:
The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Isoform 5 may play a role in spermatozoa-egg-interaction.
Gene Name:
SPAG9
Uniprot ID:
O60271
Molecular Weight:
146204.38 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
8. Estrogen receptor
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
References
  1. Zang Y, Odwin-Dacosta S, Yager JD: Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells. Toxicol Lett. 2009 Jan 30;184(2):134-8. doi: 10.1016/j.toxlet.2008.10.032. Epub 2008 Nov 11. [19041697 ]
Target Details
9. Estrogen receptor beta
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
References
  1. Zang Y, Odwin-Dacosta S, Yager JD: Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells. Toxicol Lett. 2009 Jan 30;184(2):134-8. doi: 10.1016/j.toxlet.2008.10.032. Epub 2008 Nov 11. [19041697 ]
Target Details
10. Fas-binding factor 1
General Function:
Not Available
Specific Function:
Keratin-binding protein required for epithelial cell polarization. Involved in apical junction complex (AJC) assembly via its interaction with PARD3. Required for ciliogenesis.
Gene Name:
FBF1
Uniprot ID:
Q8TES7
Molecular Weight:
125445.19 Da
References
  1. Mothes E, Faller P: Evidence that the principal CoII-binding site in human serum albumin is not at the N-terminus: implication on the albumin cobalt binding test for detecting myocardial ischemia. Biochemistry. 2007 Feb 27;46(8):2267-74. Epub 2007 Feb 3. [17274600 ]
Target Details
11. Ferritin light chain
General Function:
Iron ion binding
Specific Function:
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity).
Gene Name:
FTL
Uniprot ID:
P02792
Molecular Weight:
20019.49 Da
References
  1. Wang Z, Li C, Ellenburg M, Soistman E, Ruble J, Wright B, Ho JX, Carter DC: Structure of human ferritin L chain. Acta Crystallogr D Biol Crystallogr. 2006 Jul;62(Pt 7):800-6. Epub 2006 Jun 20. [16790936 ]
Target Details
12. Metallothionein-1A
General Function:
Zinc ion binding
Specific Function:
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Gene Name:
MT1A
Uniprot ID:
P04731
Molecular Weight:
6120.19 Da
References
  1. Sutherland DE, Willans MJ, Stillman MJ: Supermetalation of the beta domain of human metallothionein 1a. Biochemistry. 2010 May 4;49(17):3593-601. doi: 10.1021/bi1003537. [20329713 ]
Target Details
13. Metallothionein-2
General Function:
Zinc ion binding
Specific Function:
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Gene Name:
MT2A
Uniprot ID:
P02795
Molecular Weight:
6042.05 Da
References
  1. Palumaa P, Tammiste I, Kruusel K, Kangur L, Jornvall H, Sillard R: Metal binding of metallothionein-3 versus metallothionein-2: lower affinity and higher plasticity. Biochim Biophys Acta. 2005 Mar 14;1747(2):205-11. Epub 2004 Dec 19. [15698955 ]
Target Details
14. Mitogen-activated protein kinase 1
General Function:
Rna polymerase ii carboxy-terminal domain kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation.Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity.
Gene Name:
MAPK1
Uniprot ID:
P28482
Molecular Weight:
41389.265 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
15. Mitogen-activated protein kinase 10
General Function:
Map kinase kinase activity
Specific Function:
Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692).
Gene Name:
MAPK10
Uniprot ID:
P53779
Molecular Weight:
52585.015 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
16. Mitogen-activated protein kinase 11
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment.
Gene Name:
MAPK11
Uniprot ID:
Q15759
Molecular Weight:
41356.875 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
17. Mitogen-activated protein kinase 12
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
Gene Name:
MAPK12
Uniprot ID:
P53778
Molecular Weight:
41939.84 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
18. Mitogen-activated protein kinase 13
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells.
Gene Name:
MAPK13
Uniprot ID:
O15264
Molecular Weight:
42089.28 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
19. Mitogen-activated protein kinase 14
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.
Gene Name:
MAPK14
Uniprot ID:
Q16539
Molecular Weight:
41292.885 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
20. Mitogen-activated protein kinase 15
General Function:
Sh3 domain binding
Specific Function:
In vitro, phosphorylates MBP.
Gene Name:
MAPK15
Uniprot ID:
Q8TD08
Molecular Weight:
59831.645 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
21. Mitogen-activated protein kinase 3
General Function:
Phosphatase binding
Specific Function:
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.
Gene Name:
MAPK3
Uniprot ID:
P27361
Molecular Weight:
43135.16 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
22. Mitogen-activated protein kinase 4
General Function:
Protein serine/threonine kinase activity
Specific Function:
Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle (By similarity).
Gene Name:
MAPK4
Uniprot ID:
P31152
Molecular Weight:
65921.01 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
23. Mitogen-activated protein kinase 6
General Function:
Protein serine/threonine kinase activity
Specific Function:
Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle (By similarity).
Gene Name:
MAPK6
Uniprot ID:
Q16659
Molecular Weight:
82680.11 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
24. Mitogen-activated protein kinase 7
General Function:
Mitogen-activated protein kinase binding
Specific Function:
Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.
Gene Name:
MAPK7
Uniprot ID:
Q13164
Molecular Weight:
88385.515 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
25. Mitogen-activated protein kinase 8
General Function:
Protein serine/threonine kinase activity
Specific Function:
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692).JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.
Gene Name:
MAPK8
Uniprot ID:
P45983
Molecular Weight:
48295.14 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
26. Mitogen-activated protein kinase 9
General Function:
Transcription factor binding
Specific Function:
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692).MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.
Gene Name:
MAPK9
Uniprot ID:
P45984
Molecular Weight:
48138.655 Da
References
  1. Chen L, Liu L, Luo Y, Huang S: MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem. 2008 Apr;105(1):251-61. Epub 2007 Nov 16. [18021293 ]
Target Details
27. Sodium-dependent serotonin transporter
General Function:
Serotonin:sodium symporter activity
Specific Function:
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
Gene Name:
SLC6A4
Uniprot ID:
P31645
Molecular Weight:
70324.165 Da
References
  1. Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD: Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem. 2006 Jan 27;281(4):2012-23. Epub 2005 Nov 3. [16272152 ]