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Molecular and Cellular Biology, December 2007, p. 8698-8712, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00948-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Neph1 Cooperates with Nephrin To Transduce a Signal That Induces Actin Polymerization{triangledown}

Puneet Garg,1,{dagger} Rakesh Verma,1,{dagger} Deepak Nihalani,3 Duncan B. Johnstone,1 and Lawrence B. Holzman1,2*

Division of Nephrology, University of Michigan Medical School, Ann Arbor, Michigan 48109,1 Department of Veterans Affairs, Ann Arbor, Michigan 48105,2 Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana 462023

Received 29 May 2007/ Returned for modification 13 July 2007/ Accepted 28 September 2007

While the mechanisms that regulate actin dynamics in cellular motility are intensively studied, relatively little is known about signaling events that transmit outside-in signals and direct assembly and regulation of actin polymerization complexes at the cell membrane. The kidney podocyte provides a unique model for investigating these mechanisms since deletion of Nephrin or Neph1, two interacting components of the specialized podocyte intercellular junction, results in abnormal podocyte morphogenesis and junction formation. We provide evidence that extends the existing model by which the Nephrin-Neph1 complex transduces phosphorylation-mediated signals that assemble an actin polymerization complex at the podocyte intercellular junction. Upon engagement, Neph1 is phosphorylated on specific tyrosine residues by Fyn, which results in the recruitment of Grb2, an event that is necessary for Neph1-induced actin polymerization at the plasma membrane. Importantly, Neph1 and Nephrin directly interact and, by juxtaposing Grb2 and Nck1/2 at the membrane following complex activation, cooperate to augment the efficiency of actin polymerization. These data provide evidence for a mechanism reminiscent of that employed by vaccinia virus and other pathogens, by which a signaling complex transduces an outside-in signal that results in actin filament polymerization at the plasma membrane.

* Corresponding author. Mailing address: University of Michigan Medical School, Division of Nephrology, 1560 Medical Science Research Building II, Ann Arbor, MI 48109-5676. Phone: (734) 764-3157. Fax: (734) 763-0982. E-mail: lholzman{at}umich.edu

{triangledown} Published ahead of print on 8 October 2007.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, December 2007, p. 8698-8712, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00948-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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