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Molecular and Cellular Biology, November 2000, p. 8352-8363, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Platelet-Derived Growth Factor Receptor Association with Na+/H+ Exchanger Regulatory Factor Potentiates Receptor Activity

Stuart Maudsley,dagger A. Musa Zamah, Nadeem Rahman,Dagger Jeremy T. Blitzer,§ Louis M. Luttrell, Robert J. Lefkowitz,* and Randy A. Hall||

Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710

Received 15 May 2000/Returned for modification 29 June 2000/Accepted 15 August 2000

Platelet-derived growth factor (PDGF) is a potent mitogen for many cell types. The PDGF receptor (PDGFR) is a receptor tyrosine kinase that mediates the mitogenic effects of PDGF by binding to and/or phosphorylating a variety of intracellular signaling proteins upon PDGF-induced receptor dimerization. We show here that the Na+/H+ exchanger regulatory factor (NHERF; also known as EBP50), a protein not previously known to interact with the PDGFR, binds to the PDGFR carboxyl terminus (PDGFR-CT) with high affinity via a PDZ (PSD-95/Dlg/Z0-1 homology) domain-mediated interaction and potentiates PDGFR autophosphorylation and extracellular signal-regulated kinase (ERK) activation in cells. A point-mutated version of the PDGFR, with the terminal leucine changed to alanine (L1106A), cannot bind NHERF in vitro and is markedly impaired relative to the wild-type receptor with regard to PDGF-induced autophosphorylation and activation of ERK in cells. NHERF potentiation of PDGFR signaling depends on the capacity of NHERF to oligomerize. NHERF oligomerizes in vitro when bound with PDGFR-CT, and a truncated version of the first NHERF PDZ domain that can bind PDGFR-CT but which does not oligomerize reduces PDGFR tyrosine kinase activity when transiently overexpressed in cells. PDGFR activity in cells can also be regulated in a NHERF-dependent fashion by stimulation of the beta 2-adrenergic receptor, a known cellular binding partner for NHERF. These findings reveal that NHERF can directly bind to the PDGFR and potentiate PDGFR activity, thus elucidating both a novel mechanism by which PDGFR activity can be regulated and a new cellular role for the PDZ domain-containing adapter protein NHERF.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2974. Fax: (919) 684-8875. E-mail: lefko001{at}mc.duke.edu.

dagger Present address: Medical Research Council Reproductive Biology Unit, Edinburgh EH3 9EW, United Kingdom.

Dagger Present address: Department of Urology, University of California at San Francisco, San Francisco, CA 94143.

§ Present address: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.

|| Present address: Department of Pharmacology, Rollins Research Center, Emory University School of Medicine, Atlanta, GA 30322.

Molecular and Cellular Biology, November 2000, p. 8352-8363, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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