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Molecular and Cellular Biology, November 2000, p. 8352-8363, Vol. 20, No. 22
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
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


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