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Molecular and Cellular Biology, November 2000, p. 7867-7880, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Nckbeta Adapter Regulates Actin Polymerization in NIH 3T3 Fibroblasts in Response to Platelet-Derived Growth Factor bb

Min Chen,1 Hongyun She,2 Airie Kim,2 David T. Woodley,2 and Wei Li2,*

Department of Medicine, Division of Dermatology, and Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033,2 and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 606371

Received 22 May 2000/Returned for modification 10 July 2000/Accepted 27 July 2000

The SH3-SH3-SH3-SH2 adapter Nck represents a two-gene family that includes Nckalpha (Nck) and Nckbeta (Grb4/Nck2), and it links receptor tyrosine kinases to intracellular signaling networks. The function of these mammalian Nck genes has not been established. We report here a specific role for Nckbeta in platelet-derived growth factor (PDGF)-induced actin polymerization in NIH 3T3 cells. Overexpression of Nckbeta but not Nckalpha blocks PDGF-stimulated membrane ruffling and formation of lamellipoda. Mutation in either the SH2 or the middle SH3 domain of Nckbeta abolishes its interfering effect. Nckbeta binds at Tyr-1009 in human PDGF receptor beta  (PDGFR-beta ) which is different from Nckalpha 's binding site, Tyr-751, and does not compete with phosphatidylinositol-3 kinase for binding to PDGFR. Microinjection of an anti-Nckbeta but not an anti-Nckalpha antibody inhibits PDGF-stimulated actin polymerization. Constitutively membrane-bound Nckbeta but not Nckalpha blocks Rac1-L62-induced membrane ruffling and formation of lamellipodia, suggesting that Nckbeta acts in parallel to or downstream of Rac1. This is the first report of Nckbeta 's role in receptor tyrosine kinase signaling to the actin cytoskeleton.

* Corresponding author. Mailing address: Department of Medicine, Division of Dermatology, and Norris Cancer Center, University of Southern California Keck School of Medicine, 1303 North Mission Road, Los Angeles, CA 90033. Phone: (323) 224-7058. Fax: (323) 224-7679. E-mail: wli{at}hsc.usc.edu.

Molecular and Cellular Biology, November 2000, p. 7867-7880, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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