DAPK3

DAPK3 (death-associated protein kinase 3), also known as ZIPK (zipper-interacting protein kinase), is a serine/threonine kinase that regulates apoptosis, autophagy, transcription, translation, actin cytoskeleton remodeling, and smooth muscle contractility through phosphorylation-dependent signaling networks.^[1][2] Mechanistically, DAPK3 controls myosin phosphorylation by directly targeting myosin regulatory proteins and by inhibiting myosin phosphatase through phosphorylation of PPP1R12A, thereby promoting cytoskeletal reorganization and contractile responses.^[1][3] These activities position DAPK3 at the intersection of cell death signaling and cytoskeletal regulation, where its catalytic activity is required for both caspase-dependent and caspase-independent death pathways.^[3] In disease-related models, DAPK3 contributes to vascular inflammation, hypertension, intestinal epithelial homeostasis, and cancer-associated signaling pathways, highlighting its relevance in cardiovascular and inflammatory disorders as well as tumor progression.^[2][4] Compared with other DAPK family members, DAPK3 lacks the canonical calmodulin-regulatory architecture characteristic of DAPK1 while retaining a conserved serine/threonine kinase domain that mediates distinct substrate interactions and signaling outputs.^[3][5] This functional divergence supports the use of DAPK3 as a mechanistically distinct experimental target for dissecting kinase-dependent regulation of apoptosis, autophagy, and actomyosin dynamics.^[1][3] For experimental applications, emerging DAPK-family small-molecule inhibitors are being developed as pharmacological probes to investigate DAPK3-mediated signaling and disease mechanisms.^[6]