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J. Biol. Chem., Vol. 277, Issue 41, 38627-38634, October 11, 2002
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From the A variety of tumors contain activating mutations
in the cytoplasmic juxtamembrane domain of the type III family of
receptor-tyrosine kinases, and some constructed mutations in this
domain induce ligand-independent receptor activation. To explore the
role of this domain in regulation of receptor activity, we subjected
the juxtamembrane domain of the murine platelet-derived growth factor (PDGF)
Definition of an Inhibitory Juxtamembrane
WW-like Domain in the Platelet-derived Growth Factor
Receptor*
§¶,§,
,**,, and
Department of Genetics, Yale University
School of Medicine, New Haven, Connecticut 06510 and the
Center for Structural Biology, State University of New York at
Stony Brook, Stony Brook, New York 11794
receptor to alanine-scanning mutagenesis. The mutant receptors were expressed in Ba/F3 cells and tested for constitutive tyrosine phosphorylation, association with phosphatidylinositol 3'-kinase, and their ability to induce cell survival and proliferation in the absence of interleukin-3. The mutant receptors accumulated to
similar levels and appeared to undergo a normal PDGF-induced increase
in tyrosine phosphorylation. Alanine substitutions at numerous
positions located throughout the juxtamembrane domain caused
constitutive receptor activation, as did an alanine insertion in the
membrane-proximal segment of the juxtamembrane domain and a six-amino
acid deletion in the center of the domain. It is possible to model the
PDGF receptor juxtamembrane domain as a short 
-helix followed by a
three-stranded -sheet very similar to the known structures of WW
domains. Strikingly, the activating mutations clustered in the central
portions of the first and second strands and along one face of the
-sheet, whereas the loops connecting the strands were largely devoid
of mutationally sensitive positions. These findings provide strong
support for the model that the activating mutations in the
juxtamembrane region stimulate receptor activity by disrupting an
inhibitory WW-like domain.
*
This work was supported in part by National Institutes of
Health Grants CA37157 and CA85787 (to D. D.) and GM46732 (to
S. O. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. Tel.: 203-785-2684; Fax: 203-785-6765; E-mail:
daniel.dimaio@yale.edu
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