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First published online 9 June 2009
doi: 10.1242/jcs.041343

Journal of Cell Science 122, 2283-2291 (2009)
Published by The Company of Biologists 2009
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Research Article

The F-BAR protein CIP4 promotes GLUT4 endocytosis through bidirectional interactions with N-WASp and Dynamin-2

Sean M. Hartig1,2, Shuhei Ishikura3, Rachel S. Hicklen1, Yanming Feng1,4, Elisabeth G. Blanchard1, Kevin A. Voelker5, Christina S. Pichot1, Robert W. Grange5, Robert M. Raphael6, Amira Klip3 and Seth J. Corey1,4,*

1 Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
3 Cell Biology Program, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
4 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
5 Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
6 Department of Bioengineering, Rice University, Houston, TX 77005, USA

* Author for correspondence (e-mail: s-corey{at}northwestern.edu)

Accepted 31 March 2009

F-BAR proteins are a newly described family of proteins with unknown physiological significance. Because F-BAR proteins, including Cdc42 interacting protein-4 (CIP4), drive membrane deformation and affect endocytosis, we investigated the role of CIP4 in GLUT4 traffic by flow cytometry in GLUT4myc-expressing L6 myoblasts (L6 GLUT4myc). L6 GLUT4myc cells express CIP4a as the predominant F-BAR protein. siRNA knockdown of CIP4 increased insulin-stimulated 14C-deoxyglucose uptake by elevating cell-surface GLUT4. Enhanced surface GLUT4 was due to decreased endocytosis, which correlated with lower transferrin internalization. Immunoprecipitation of endogenous CIP4 revealed that CIP4 interacted with N-WASp and Dynamin-2 in an insulin-dependent manner. FRET confirmed the insulin-dependent, subcellular properties of these interactions. Insulin exposure stimulated specific interactions in plasma membrane and cytosolic compartments, followed by a steady-state response that underlies the coordination of proteins needed for GLUT4 traffic. Our findings reveal a physiological function for F-BAR proteins, supporting a previously unrecognized role for the F-BAR protein CIP4 in GLUT4 endocytosis, and show that interactions between CIP4 and Dynamin-2 and between CIP4 and NWASp are spatially coordinated to promote function.

Key words: F-BAR, N-WASp, Endocytosis


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