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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cell Line
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Cell Movement / genetics
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Cell Movement / physiology*
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Cell Polarity / genetics
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Cell Polarity / physiology*
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Death-Associated Protein Kinases
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Humans
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Integrin beta1 / metabolism*
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Mice
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / pathology
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Neoplasms / metabolism
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Neoplasms / pathology
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Protein Structure, Tertiary
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RNA, Small Interfering / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Talin / antagonists & inhibitors
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Talin / genetics
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Talin / metabolism
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
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cdc42 GTP-Binding Protein / antagonists & inhibitors
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cdc42 GTP-Binding Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Integrin beta1
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RNA, Small Interfering
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Talin
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Tumor Suppressor Proteins
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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cdc42 GTP-Binding Protein