Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 31 March 2009
Vol. 2, Issue 64, p. ec115
[DOI: 10.1126/scisignal.264ec115]


Biochemistry Bringing Src to the Phosphatase

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

The activity of the tyrosine kinase Src is frequently elevated in cancers; however, the mechanism by which increased Src activity occurs is unknown. Zhang et al. developed an antibody that recognizes reversion-induced LIM (RIL), a protein encoded by a gene that is hypermethylated in cancer cell lines and various tumors, and showed that this protein was absent from several colon cancer cell lines, although it could be detected in other cell lines. Forced expression of RIL reduced the phosphorylation of the active site of Src (pY419) and the phosphorylation of focal adhesion kinase (a substrate of Src) in the colon cancer cell line HCT116. Furthermore, forced expression of RIL decreased anchorage-independent growth, which was reversed by expression of constitutively active Src. In WI-38 cells containing endogenous RIL, RIL colocalized with Src in some areas but was notably not present in areas where active Src (pY419 Src) was abundant (peripheral structures that may be focal adhesion sites). Several different experiments, including glutathione S-transferase (GST) fusion protein pull-down experiments and coimmunoprecipitation of endogenous proteins, suggested that RIL and Src directly interacted. Furthermore, the interaction appeared to occur with RIL and pY419 Src. The interaction of purified Src with GST-RIL did not inhibit Src activity; however, overexpressed RIL coprecipitated with the phosphatase PTPL1 (protein tyrosine phosphatase BAS-like), and this required the LIM domain of RIL. Src phosphorylation was not reduced by expression of RIL with deletions of the PTPL1 binding domain or expression of wild-type RIL in cells in which PTPL1 was knocked down. Whereas wild-type Src or a kinase-activated Src mutant readily bound GST-RIL, mutating the active-site tyrosine prevented binding to RIL. The authors propose that RIL recognizes pY419 Src and brings this kinase into proximity of PTPL1, which dephosphorylates Src, so that Src is released from RIL. Thus, RIL maintains the proper balance of active Src by serving as a bridge to the Src phosphatase and, in cells lacking RIL, Src remains in an active state.

Y. Zhang, Y. Tu, J. Zhao, K. Chen, C. Wu, Reversion-induced LIM interaction with Src reveals a novel Src inactivation cycle. J. Cell Biol. 184, 785–792 (2009). [Abstract] [Full Text]

Citation: N. R. Gough, Bringing Src to the Phosphatase. Sci. Signal. 2, ec115 (2009).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882