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MBC in Press, published online ahead of print September 26, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0550

A more recent version of this article appeared on December 1, 2007
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Submitted on June 11, 2007
Revised on September 7, 2007
Accepted on September 13, 2007

Identification of an Intramolecular Interaction Important for the Regulation of GIT1 Functions

Antonio Totaro, Simona Paris, Claudia Asperti, and Ivan de Curtis

Cell Adhesion Unit, Dibit, San Raffaele Scientific Institute, 20132 Milano, Italy

Monitoring Editor: Josephine Adams

GIT proteins include an N-terminal ArfGAP domain, and a C-terminus that binds proteins regulating adhesion and motility. Given their ability to form large molecular assemblies, the GIT1 protein must be tightly regulated. However, the mechanisms regulating GIT1 functions are poorly characterized. We found that carboxyterminal truncated fragments of GIT1 bind their partners with higher efficiency compared with the full-length GIT1. We have explored the hypothesis that GIT1 is regulated by an intramolecular mechanism, and identified two distinct intramolecular interactions between the N- and C-terminus of GIT1. The release of these interactions increases binding of GIT1 to paxillin and liprin-{alpha}, and correlates with effects on cell spreading. Analysis of cells plated on fibronectin has shown that different deletion mutants of GIT1 either enhance or inhibit spreading, depending on their subcellular localization. Moreover, while the association between {beta}PIX and GIT1 is insufficient to activate GIT1 binding to paxillin, binding of a PAK1 fragment including the {beta}PIX-binding domain enhances paxillin binding to {beta}PIX/GIT1, indicating that PAK can activate the binding of paxillin to GIT1 by a kinase-independent mechanism. The release of the identified intramolecular interaction appears to be an important mechanism for the regulation of GIT1 functions.

Address correspondence to: Ivan de Curtis (decurtis.ivan{at}hsr.it)






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