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J. Cell Biol. 184 (6): 785-792

Copyright © 2009 by the Rockefeller University Press.

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Reversion-induced LIM interaction with Src reveals a novel Src inactivation cycle

Yongjun Zhang, Yizeng Tu, Jianping Zhao, Ka Chen, , and Chuanyue Wu

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261

Correspondence to Chuanyue Wu: carywu{at}pitt.edu

Abstract: Aberrant Src activation plays prominent roles in cancer progression. However, how Src is activated in cancer cells is largely unknown. Genetic Src-activating mutations are rare and, therefore, are insufficient to account for Src activation commonly found in human cancers. In this study, we show that reversion-induced LIM (RIL), which is frequently lost in colon and other cancers as a result of epigenetic silencing, suppresses Src activation. Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1-dependent dephosphorylation of Src at the activation loop. Importantly, the binding of RIL to Src is drastically reduced upon Src inactivation. Our results reveal a novel Src inactivation cycle in which RIL preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src. Inactivation of Src, in turn, promotes dissociation of RIL from Src, allowing the initiation of a new Src inactivation cycle. Epigenetic silencing of RIL breaks this Src inactivation cycle and thereby contributes to aberrant Src activation in human cancers.

Abbreviations used in this paper: BL, BAS-like; MBP, maltose-binding protein; PTP, protein Tyr phosphatase; RIL, reversion-induced LIM.

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