MAP3K7
Description
The MAP3K7 (mitogen-activated protein kinase kinase kinase 7) is a protein-coding gene located on chromosome 6.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.
== Structure == TAK1 is an evolutionarily conserved kinase in the MAP3 K family and clusters with the tyrosine-like and sterile kinase families. The protein structure of TAK1 contains an N (residues 1–104)- and C (residues 111–303)-terminus connected through the hinge region (Met 104-Ser 111). The ATP binding pocket is located in the hinge region of the kinase. Additionally, TAK1 has a catalytic lysine (Lys63) in the active site. Crystal structure of TAK1-ATP have shown that ATP forms two hydrogen bonds with residues Ala 107 and Glu 105. Further hydrogen bonding is observed to Asp 175, which is the leading residue of the DFG motif. This residue is thought to interact with Lys 63 through polar interactions and is catalytically important for phosphate transfer to substrate molecules. Critical for the TAK1-TAB1 complex is a helical loop around Phe 484, which provides extensive surface contact between the two proteins.
== Signaling == The protein encoded by this gene is a member of the serine/threonine protein kinase family.
MAP3K7 (also known as TAK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signal transduction pathway. It is involved in cellular responses to environmental changes, mediating signal transduction from various sources like TRAF6, cytokines (IL-1, TGFB), TGFB-related factors (BMP2, BMP4), TLRs, CD40, and BCR. Upon activation, MAP3K7 acts upstream of the MKK/JNK and p38 MAPK cascades, activating MAP kinase kinases (MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6, MAP2K7/MKK7) that in turn activate p38 MAPKs and JNKs, both of which regulate the transcription factor AP-1. MAP3K7 also independently activates NF-kappa-B by promoting IKK complex activation. It is recruited to polyubiquitin chains of RIPK2 and IKBKG/NEMO through TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3, leading to phosphorylation and activation of IKBKB/IKKB. In osmotic stress, MAP3K7 primarily activates MAPK8/JNK1 but not NF-kappa-B. It also enhances TRIM5 capsid-specific restriction activity. MAP3K7 phosphorylates RIPK1 at 'Ser-321', positively regulating RIPK1 interaction with RIPK3 for necroptosis but negatively regulating RIPK1 kinase activity and its interaction with FADD for apoptosis. MAP3K7 phosphorylates STING1 upon cGAMP activation, promoting STEEP1-STING1 association and STING1 translocation to COPII vesicles.
MAP3K7 is also known as CSCF, FMD2, MEKK7, TAK1, TGF1a.
