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

doi:10.1128/MCB.20.22.8352-8363.2000

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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, A. Musa Zamah, Nadeem Rahman, 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 tyrosinekinase that mediates the mitogenic effects of PDGF by bindingto and/or phosphorylating a variety of intracellular signalingproteins upon PDGF-induced receptor dimerization. We show herethat the Na⁺/H⁺ exchanger regulatory factor (NHERF; also known as EBP50), a proteinnot previously known to interact with the PDGFR, binds to thePDGFR carboxyl terminus (PDGFR-CT) with high affinity via a PDZ(PSD-95/Dlg/Z0-1 homology) domain-mediated interaction and potentiatesPDGFR 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), cannotbind NHERF in vitro and is markedly impaired relative to the wild-typereceptor with regard to PDGF-induced autophosphorylation and activationof ERK in cells. NHERF potentiation of PDGFR signaling dependson the capacity of NHERF to oligomerize. NHERF oligomerizes invitro when bound with PDGFR-CT, and a truncated version of thefirst NHERF PDZ domain that can bind PDGFR-CT but which does notoligomerize reduces PDGFR tyrosine kinase activity when transientlyoverexpressed in cells. PDGFR activity in cells can also be regulatedin a NHERF-dependent fashion by stimulation of the $beta$ ₂-adrenergicreceptor, a known cellular binding partner for NHERF. These findingsreveal that NHERF can directly bind to the PDGFR and potentiatePDGFR activity, thus elucidating both a novel mechanism by whichPDGFR activity can be regulated and a new cellular role for thePDZ domain-containing adapter proteinNHERF.

^* 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.

Present address: Medical Research Council Reproductive Biology Unit, Edinburgh EH3 9EW, UnitedKingdom.

Present address: Department of Urology, University of California at San Francisco, San Francisco, CA94143.

^§ Present address: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA94305.

Present address: Department of Pharmacology, Rollins Research Center, Emory University School of Medicine, Atlanta, GA30322.

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