Protein / target

Mitogen-activated protein kinase kinase kinase 5

Encoded byMAP3K5Q99683Homo sapiensSwiss-Prot

UniProt: Q99683 Ensembl: ENSG00000197442 HGNC: HGNC:6857 NCBI Gene: 4217

Clinical-stage

Therapeutic maturity

Clinical candidates

Small-molecule tractable

Druggability

Advanced Clinical

Research papers

Protein at a glance

Biological role

Protein serine/threonine kinase

Strongest disease association

Smoking initiation

Via encoding gene MAP3K5 · Genetic evidence · score 0.54

Therapeutic position

Clinically advancing target

Small molecules

Research activity

Emerging research

1 papers · latest 2024

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

View complete UniProt function annotation

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)

Subcellular location

CytoplasmEndoplasmic reticulum

Domains and Gene Ontology detail (36)

Domains & features

Protein kinase

Gene Ontology

Ccytoplasm
Ccytosol
CIRE1-TRAF2-ASK1 complex
Cprotein kinase complex
Cprotein-containing complex
FATP binding
Fidentical protein binding
FJUN kinase kinase kinase activity
Fmagnesium ion binding
FMAP kinase kinase kinase activity
Fprotein domain specific binding
Fprotein homodimerization activity

1374 aa · 155 kDa · 2 isoforms

Biological roles

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Kinase signallingUniProt · GOApoptosis & cell deathUniProt · GOImmune signallingUniProt · GOTranscriptional regulationUniProt · GO

View supporting evidence

Kinase signalling

·Serine/threonine kinase which acts as an essential component of the MAP kinase signal tr…
·protein kinase complex
·JUN kinase kinase kinase activity
·MAP kinase kinase kinase activity

Apoptosis & cell death

·Serine/threonine kinase which acts as an essential component of the MAP kinase signal tr…
·neuron apoptotic process
·positive regulation of apoptotic process

Immune signalling

·Serine/threonine kinase which acts as an essential component of the MAP kinase signal tr…
·innate immune response

Transcriptional regulation

·Serine/threonine kinase which acts as an essential component of the MAP kinase signal tr…
·positive regulation of DNA-templated transcription

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene MAP3K5

Gene-level evidence surfaced through the gene MAP3K5that encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Smoking initiation

0.54Moderately supported

Genetic evidence dominant · Open Targets 0.33

Parkinson's Disease

0.43Limited support

Genetic evidence dominant · Open Targets 0.25

Infertility, Male

0.40Limited support

Genetic evidence dominant · Open Targets 0.24

Non-alcoholic Fatty Liver Disease

0.30Limited support

Clinical evidence dominant · Open Targets 0.20

Diabetic Nephropathies

0.20Preliminary

Clinical evidence dominant · Open Targets 0.12

View evidence synthesis (5)

Smoking initiationModerately supported

0.54

agreement 0.42–0.66

Genetic100%

Open Targets aggregate 0.33 · 1 independent evidence family

Parkinson's DiseaseLimited support

0.43

agreement 0.29–0.57

Genetic90%Literature10%

Open Targets aggregate 0.25 · 2 independent evidence families

Infertility, MaleLimited support

0.40

agreement 0.26–0.54

Genetic100%Literature1%

Open Targets aggregate 0.24 · 2 independent evidence families

Non-alcoholic Fatty Liver DiseaseLimited support

0.30

agreement 0.14–0.45

Clinical69%Literature31%

Open Targets aggregate 0.20 · 2 independent evidence families

Diabetic NephropathiesPreliminary

0.20

agreement 0.05–0.36

Clinical58%Literature42%

Open Targets aggregate 0.12 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations

Smoking initiation0.33

Parkinson's Disease0.25

Infertility, Male0.24

Neurodegenerative Diseases0.24

Non-alcoholic Fatty Liver Disease0.20

Fibrosis0.15

Diabetic Nephropathies0.12

Pulmonary arterial hypertension0.10

Drug development

1 compounds recorded · 1 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines.

View all recorded compounds (1)

SELONSERTIBPhase 3

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Strong

Advanced Clinical and Structure with Ligand support this modality.

Protein degraders — Emerging

Feasibility evidence (uniprot ubiquitination and database ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (9)

SM · Advanced ClinicalSM · Structure with LigandSM · High-Quality LigandSM · High-Quality PocketSM · Druggable FamilyPR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

heart diseaseForce et al. (2011)

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Research activity

1 papers · to 2024

Papers linked directly to this protein. This is the protein's own literature — descriptor-derived papers are kept separate below.

Most cited

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.23 cites

Zhang KH · Protein & cell · 2024

Recent

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.

Zhang KH · Protein & cell · 2024

Europe PMC papers linked directly to this protein.