The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway.
Death-associated protein kinase (DAPK) is a calmodulin-regulated serine/threonine kinase and possesses apoptotic and tumor-suppressive functions. However, it is unclear whether DAPK elicits apoptosis-independent activity to suppress tumor progression. We show that DAPK inhibits random migration by reducing directional persistence and directed migration by blocking cell polarization. These effects are mainly mediated by an inhibitory role of DAPK in talin head domain association with integrin, thereby suppressing the integrin-Cdc42 polarity pathway. We present evidence indicating that the antimigratory effect of DAPK represents a mechanism through which DAPK suppresses tumors. First, DAPK can block migration and invasion in certain tumor cells that are resistant to DAPK-induced apoptosis. Second, using an adenocarcinoma cell line and its highly invasive derivative, we demonstrate DAPK level as a determining factor in tumor invasiveness. Collectively, our study identifies a novel function of DAPK in regulating cell polarity during migration, which may act together with its apoptotic function to suppress tumor progression.
Kuo
Jean-Cheng
JC
Institute of Molecular Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 106, Taiwan.
Wang
Won-Jing
WJ
Yao
Chung-Chen
CC
Wu
Pei-Rung
PR
Chen
Ruey-Hwa
RH
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D064550:Death-Associated Protein Kinases; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016608:Talin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D019012:Integrin beta1; D034741:RNA, Small Interfering; D016608:Talin; D025521:Tumor Suppressor Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020764:cdc42 GTP-Binding Protein