MAP3K5
Description
The MAP3K5 (mitogen-activated protein kinase kinase kinase 5) is a protein-coding gene located on chromosome 6.
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases. MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33. and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.
== Mechanism of activation == Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator.
MAP3K5, also known as ASK1, is a serine/threonine kinase that plays a crucial role in the MAP kinase signal transduction pathway. It responds to environmental changes and mediates signaling for important cellular processes like differentiation and survival. MAP3K5 is particularly important in the apoptosis signal transduction pathway, contributing to mitochondria-dependent caspase activation. It is also essential for the innate immune response, defending the host against a variety of pathogens. MAP3K5 is activated by various stressors, including oxidative stress, and by inflammatory signals such as TNF and LPS. Once activated, MAP3K5 acts upstream to activate the MKK/JNK and p38 MAPK signal transduction cascades. It phosphorylates and activates MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6, and MAP2K7/MKK7, which in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs regulate the transcription factors activator protein-1 (AP-1).
MAP3K5 is also known as ASK1, MAPKKK5, MEKK5.
