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Published 13 February 2006. doi:10.1083/jcb.200505138
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 619-631
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Article

 The tumor suppressor DAPK inhibits cell motility by blocking the integrin-mediated polarity pathway

Jean-Cheng Kuo1, Won-Jing Wang1, Chung-Chen Yao2,3, Pei-Rung Wu1, and Ruey-Hwa Chen1

1 Institute of Molecular Medicine and 2 Department of Orthodontics, College of Medicine, and 3 Department of Dentistry, National Taiwan University Hospital, National Taiwan University, Taipei 106, Taiwan

Correspondence to Ruey-Hwa Chen: rhchen{at}ha.mc.ntu.edu.tw

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.

Abbreviations used in this paper: DAPK, Death-associated protein kinase; MLC, myosin light chain; MTOC, microtubule-organizing center; pFAK, phosphorylated FAK; siRNA, small interfering RNA; talin-H, talin head domain.


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