The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway
Journal
Journal of Cell Biology
Journal Volume
172
Journal Issue
4
Pages
619-631
Date Issued
2006
Author(s)
Abstract
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. ? The Rockefeller University Press.
SDGs
Other Subjects
death associated protein kinase; integrin; protein Cdc42; talin; adenocarcinoma; animal cell; apoptosis; article; cancer growth; cancer inhibition; cancer invasion; cell invasion; cell line; cell migration; cell motility; cell polarity; controlled study; embryo; human; human cell; mouse; nonhuman; priority journal; protein analysis; protein domain; protein function; protein protein interaction; Animals; Antigens, CD29; Apoptosis Regulatory Proteins; Ca(2+)-Calmodulin Dependent Protein Kinase; cdc42 GTP-Binding Protein; Cell Line; Cell Movement; Cell Polarity; Humans; Mice; Neoplasm Invasiveness; Neoplasms; Protein Structure, Tertiary; RNA, Small Interfering; Signal Transduction; Talin; Tumor Suppressor Proteins; Animalia
Type
journal article