Target Information
Target General Infomation | |||||
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Target ID |
T79798
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Former ID |
TTDC00044
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Target Name |
MAP kinase p38
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Gene Name |
MAPK12
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Synonyms |
ERK-6; ERK5; ERK6; Extracellular signal-regulated kinase 6; MAP kinase p38 gamma; Mitogen-activated proteinkinase 12; Mitogen-activated proteinkinase p38 gamma; SAPK3; Stress-activated protein kinase 3; MAPK12
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Target Type |
Clinical Trial
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Disease | Diabetic nephropathy [ICD9: 250.4; ICD10: E11.21] | ||||
Inflammatory bowel disease [ICD9: 555, 556; ICD10: K50, K51] | |||||
Inflammatory bowel disease; Rheumatoid arthritis; Cardiovascular disorders; Psoriasis [ICD9: 390-459, 555, 556, 696, 710-719, 714; ICD10: I00-I99, K50, K51, L40, M00-M25, M05-M06] | |||||
Osteoarthritis; Pain [ICD9: 338, 715,780; ICD10: M15-M19, M47, R52, G89] | |||||
Rheumatoid arthritis; Myelodysplastic syndrome [ICD9:710-719, 714, 238.7; ICD10: M05-M06, D46] | |||||
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.
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BioChemical Class |
Kinase
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Target Validation |
T79798
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UniProt ID | |||||
EC Number |
EC 2.7.11.24
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Sequence |
MSSPPPARSGFYRQEVTKTAWEVRAVYRDLQPVGSGAYGAVCSAVDGRTGAKVAIKKLYR
PFQSELFAKRAYRELRLLKHMRHENVIGLLDVFTPDETLDDFTDFYLVMPFMGTDLGKLM KHEKLGEDRIQFLVYQMLKGLRYIHAAGIIHRDLKPGNLAVNEDCELKILDFGLARQADS EMTGYVVTRWYRAPEVILNWMRYTQTVDIWSVGCIMAEMITGKTLFKGSDHLDQLKEIMK VTGTPPAEFVQRLQSDEAKNYMKGLPELEKKDFASILTNASPLAVNLLEKMLVLDAEQRV TAGEALAHPYFESLHDTEDEPQVQKYDDSFDDVDRTLDEWKRVTYKEVLSFKPPRQLGAR VSKETPL |
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Drugs and Mode of Action | |||||
Drug(s) | ARRY-797 | Drug Info | Phase 2 | Osteoarthritis; Pain | [547810] |
CI-1040 | Drug Info | Phase 2 | Discovery agent | [521505], [541019] | |
VX-745 | Drug Info | Phase 2 | Rheumatoid arthritis; Myelodysplastic syndrome | [525164], [541057], [544340] | |
SMP-534 | Drug Info | Preclinical | Diabetic nephropathy | [536836] | |
BIRB 796 | Drug Info | Discontinued in Phase 2 | Inflammatory bowel disease | [541011], [547541] | |
KC706 | Drug Info | Discontinued in Phase 2 | Inflammatory bowel disease; Rheumatoid arthritis; Cardiovascular disorders; Psoriasis | [548224] | |
Inhibitor | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [527308] | ||
ARRY-797 | Drug Info | [550225] | |||
BIRB 796 | Drug Info | [536977], [537039] | |||
BISINDOLYLMALEIMIDE IX | Drug Info | [525872] | |||
CI-1040 | Drug Info | [525872] | |||
GF-109203 | Drug Info | [525872] | |||
KC706 | Drug Info | [549786] | |||
KN-62 | Drug Info | [525872] | |||
KT-5720 | Drug Info | [525872] | |||
ML-3163 | Drug Info | [526355] | |||
ML-3375 | Drug Info | [526668] | |||
ML-3403 | Drug Info | [526668] | |||
Phosphoaminophosphonic Acid-Adenylate Ester | Drug Info | [551374] | |||
Phosphonothreonine | Drug Info | [551393] | |||
RO-316233 | Drug Info | [525872] | |||
RWJ-68354 | Drug Info | [526530] | |||
SMP-534 | Drug Info | [536836] | |||
STAUROSPORINONE | Drug Info | [525872] | |||
VK-19911 | Drug Info | [526904] | |||
VX-745 | Drug Info | [536458], [536961] | |||
Pathways | |||||
KEGG Pathway | MAPK signaling pathway | ||||
Rap1 signaling pathway | |||||
FoxO signaling pathway | |||||
Sphingolipid signaling pathway | |||||
Oocyte meiosis | |||||
Adrenergic signaling in cardiomyocytes | |||||
VEGF signaling pathway | |||||
Osteoclast differentiation | |||||
Signaling pathways regulating pluripotency of stem cells | |||||
Platelet activation | |||||
Toll-like receptor signaling pathway | |||||
NOD-like receptor signaling pathway | |||||
RIG-I-like receptor signaling pathway | |||||
T cell receptor signaling pathway | |||||
Fc epsilon RI signaling pathway | |||||
TNF signaling pathway | |||||
Leukocyte transendothelial migration | |||||
Neurotrophin signaling pathway | |||||
Retrograde endocannabinoid signaling | |||||
Dopaminergic synapse | |||||
Inflammatory mediator regulation of TRP channels | |||||
GnRH signaling pathway | |||||
Progesterone-mediated oocyte maturation | |||||
Prolactin signaling pathway | |||||
Amyotrophic lateral sclerosis (ALS) | |||||
Epithelial cell signaling in Helicobacter pylori infection | |||||
Shigellosis | |||||
Salmonella infection | |||||
Pertussis | |||||
Leishmaniasis | |||||
Chagas disease (American trypanosomiasis) | |||||
Toxoplasmosis | |||||
Tuberculosis | |||||
Hepatitis C | |||||
Influenza A | |||||
Epstein-Barr virus infection | |||||
Proteoglycans in cancer | |||||
NetPath Pathway | TCR Signaling Pathway | ||||
PANTHER Pathway | Alzheimer disease-amyloid secretase pathway | ||||
B cell activation | |||||
EGF receptor signaling pathway | |||||
FGF signaling pathway | |||||
Interferon-gamma signaling pathway | |||||
Oxidative stress response | |||||
Parkinson disease | |||||
TGF-beta signaling pathway | |||||
Ras Pathway | |||||
p53 pathway feedback loops 2 | |||||
p38 MAPK pathway | |||||
Pathway Interaction Database | RhoA signaling pathway | ||||
Signaling mediated by p38-gamma and p38-delta | |||||
Reactome | NOD1/2 Signaling Pathway | ||||
p38MAPK events | |||||
Activation of PPARGC1A (PGC-1alpha) by phosphorylation | |||||
CDO in myogenesis | |||||
DSCAM interactions | |||||
VEGFA-VEGFR2 Pathway | |||||
WikiPathways | Toll-like receptor signaling pathway | ||||
Insulin Signaling | |||||
MAPK Cascade | |||||
MAPK Signaling Pathway | |||||
Nanoparticle-mediated activation of receptor signaling | |||||
Signal Transduction of S1P Receptor | |||||
Parkinsons Disease Pathway | |||||
miR-targeted genes in muscle cell - TarBase | |||||
miR-targeted genes in lymphocytes - TarBase | |||||
NGF signalling via TRKA from the plasma membrane | |||||
Myogenesis | |||||
Integrin-mediated Cell Adhesion | |||||
DSCAM interactions | |||||
Regulation of toll-like receptor signaling pathway | |||||
References | |||||
Ref 521505 | ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 525164 | ClinicalTrials.gov (NCT02423200) Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX-745, in Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD. U.S. National Institutes of Health. | ||||
Ref 536836 | Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63. | ||||
Ref 541011 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5668). | ||||
Ref 541019 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676). | ||||
Ref 541057 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5719). | ||||
Ref 544340 | Myelodysplastic Syndromes: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2011 January; 9(1): 30-56. | ||||
Ref 547541 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017152) | ||||
Ref 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 526355 | J Med Chem. 2002 Jun 20;45(13):2733-40.From imidazoles to pyrimidines: new inhibitors of cytokine release. | ||||
Ref 526530 | Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.Imidazopyrimidines, potent inhibitors of p38 MAP kinase. | ||||
Ref 526668 | J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. | ||||
Ref 526904 | J Med Chem. 2003 Dec 18;46(26):5651-62.Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity. | ||||
Ref 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 536458 | Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Sep 15;17(18):5107-10. Epub 2007 Jul 13. | ||||
Ref 536836 | Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63. | ||||
Ref 536961 | P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22. | ||||
Ref 536977 | Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. Biochem J. 2009 Mar 15;418(3):625-34. |
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