Molecular Target Synopsis
Domains and Structures
Drugs and Clinical Candidates
Ligand Efficiency Plot
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
Germline Genetics

MAP3K5 (Q99683) - Overview - Molecular Target Synopsis


MAP3K5, Mitogen-activated protein kinase kinase kinase 5
Enzyme Classification
UniProt Q99683

Also Known as M3K5_HUMAN, MAP3K5, ASK1, MAPKKK5, MEKK5

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF (PubMed:15310755, PubMed:15701637, PubMed:17210579, PubMed:17389591). This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN (PubMed:10411906, PubMed:15023544, PubMed:15094778). Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN (PubMed:9564042,PubMed:9774977, PubMed:10688666, PubMed:11090355, PubMed:11689443, PubMed:12556535, PubMed:12813029, PubMed:15310755, PubMed:16038411, PubMed:16129676, PubMed:16407264, PubMed:17220297, PubMed:17724081, PubMed:18408005, PubMed:19590015, PubMed:19749799). Interacts with ERN1 in a TRAF2-dependent manner (PubMed:14749717). Interacts with calcineurin subunit PPP3R1 and with PPM1L (PubMed:17456047) (By similarity). Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5 (PubMed:11427728). Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:15310755). Interacts with DUSP13/DUSP13A; may positively regulate apoptosis (PubMed:20358250). Interacts with DAXX (PubMed:9743501). Interacts with RC3H2 (PubMed:24448648).

Inspect Structure
See all 3D Structures for MAP3K5

Isoforms / Transcripts (Protein Coding)

Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform

Sub-cellular localization

UniProt: MAP3K5 is active in the following subcellular-locations: cytoplasm, endoplasmic reticulum.
GO terms: MAP3K5 is active in the following subcellular-locations: cytosol, external side of plasma membrane, IRE1-TRAF2-ASK1 complex, protein kinase complex, protein-containing complex.

GO terms

Gene Copy Number Variation

In COSMIC - Cell Lines Project MAP3K5 has gain in 3 cell-lines, loss in 2 cell-lines and no signal in 1000 cell-lines. (see details)

Gene Expression

In NCI60, the highest expressing cell lines are: COLO205, SNB_19, OVCAR_5

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: RT4, Hs 675.T, SW 900

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HSMM, NHLF, AG445

(see details)

RNA Interference

MAP3K5 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: OVTOKO, OAW42. (see details)

3D Structures

For MAP3K5 there are:
20 structures (44 chains) solved
18 are solved in complex with at least one small molecule ligand

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry

MAP3K5 has been screened with 850 compounds (1292 bioactivities), 102 compounds have bioactivities that show binding affinity of <= 500nM (133 bioactivities). (see details)