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mitogen-activated protein kinase kinase kinase 5 (MAP3K5, MAPK/ERK kinase kinase 5, MEKK5, apoptosis signal-regulating kinase 1, ASK-1, ASK1, MAPKKK5)
Function:
- activates SEK1-JNK & MKK3/MKK6-p38 signaling cascades [2]
- activated by TNF & activates JNK/SAPK
- component of a protein kinase signal transduction cascade
- phosphorylates & activates MAP2K4 & MAP2K6, which in turn activate the JNK & p38 MAP kinases, respectively
- overexpression induces apoptotic cell death
- contains an N-terminal autoinhibitory domain
- activated by phosphorylation at Thr-838
- inhibited by phosphorylation at Ser-966 & Ser-1033
- binds to, & stabilizes MAP3K6 & is activated by MAP3K6 by phosphorylation on Thr-838
- binds both upstream activators & downstream substrates in multimolecular complexes
- associates with & inhibited by HIV-1 Nef
- interacts with DAB2IP
ATP + a protein ADP + a phosphoprotein
Cofactor: Mg+2
Structure:
- homodimer when inactive
- belongs to the protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase kinase subfamily
- contains 1 protein kinase domain
Expression:
- abundantly expressed in heart & pancreas
- induced by TNF-alpha
- inhibited by HIV-1 Nef.
Interactions
molecular events
General
mitogen-activated protein kinase kinase kinase (MAP3K) or MEK kinase (MEKK)
Properties
SIZE: entity length = 1374 aa
MW = 155 kD
STATE: active state
MOTIF: kinase domain
SITE: 680-938
MOTIF: ATP-binding site
NAME: ATP-binding site
SITE: 686-694
ATP-binding site
NAME: ATP-binding site
SITE: 709-709
aspartate residue {D803}
Thr phosphorylation site {T838}
Ser phosphorylation site {S958}
Ser phosphorylation site {S966}
Ser phosphorylation site {S1033}
References
- UniProt :accession Q99683
- Nishitoh et al. Molecular Cell 2:389-395, 1998
Databases & Figures
OMIM 602448
UniProt Q99683
Pfam PF00069
Entrez Gene 4217
ENZYME 2.7.11.25
MAP kinase pathways