Apoptosis signal-regulating kinase-1 (ASK1, MEKK5, MAPKKK5) is a MAP3k type protein kinase belonging to mitogen-activated protein kinase kinase kinase (MAPKKK) family. As a regulator of JNK and p38 MAPK signaling pathways, ASK1/MEKK5 phosphorylates MMK4 to activate c-Jun N-terminal kinase (JNK) and phosphorylates MEK3 and MKK6 to activate p38. ASK1/MEKK5 is activated by oxidative stress, TNF via TRAF2, Fas via Daxx, calcium overload, and endoplasmic reticulum stress (1). ASK1/MEKK5 is inactivated by Trx, Grx, 14-3-3, and protein serine/threonine phosphatase 5 (2). While elevated level of ASK1/MEKK5 can induce apoptosis, a catalytically inactive ASK1/MEKK5 acts as an inhibitor in TNF-alpha induced apoptosis. Over-expression of ASK1/MEKK5 has also been implicated in cell differentiation, such as in keratinocyte differentiation through p38 pathway (3). ASK1/MEKK5 has been implicated as a therapeutic target for neurodegenerative disorder sand cardiac dysfunction (4)
MAPK signaling pathway
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