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Mol Cell Biol, April 1998, p. 2089-2099, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

SHP-1 Binds and Negatively Modulates the c-Kit Receptor by Interaction with Tyrosine 569 in the c-Kit Juxtamembrane Domain

Maya Kozlowski,1,* Louise Larose,2 Fai Lee,1 Duc Mingh Le,1 Robert Rottapel,3 and Katherine A. Siminovitch4

Health Canada Life Sciences and the University of Ottawa, Ottawa,1 Polypeptide Hormone Laboratory, McGill University, Montreal,2 and Departments of Medicine, Immunology and Medical Genetics and Microbiology, University of Toronto, the Wellesley Hospital Research Institute, Wellesley Hospital,3 and the Samuel Lunenfeld Research Institute, Mount Sinai Hospital,4 Toronto, Canada

Received 17 July 1997/Returned for modification 1 September 1997/Accepted 22 December 1997

The SH2 domain-containing SHP-1 tyrosine phosphatase has been shown to negatively regulate a broad spectrum of growth factor- and cytokine-driven mitogenic signaling pathways. Included among these is the cascade of intracellular events evoked by stem cell factor binding to c-Kit, a tyrosine kinase receptor which associates with and is dephosphorylated by SHP-1. Using a series of glutathione S-transferase (GST) fusion proteins containing either tyrosine-phosphorylated segments of the c-Kit cytosolic region or the SH2 domains of SHP-1, we have shown that SHP-1 interacts with c-Kit by binding selectively to the phosphorylated c-Kit juxtamembrane region and that the association of c-Kit with the larger of the two SHP-1 isoforms may be mediated through either the N-terminal or C-terminal SHP-1 SH2 domain. The results of binding assays with mutagenized GST-Kit juxtamembrane fusion proteins and competitive inhibition assays with phosphopeptides encompassing each c-Kit juxtamembrane region identified the tyrosine residue at position 569 as the major site for binding of SHP-1 to c-Kit and suggested that tyrosine 567 contributes to, but is not required for, this interaction. By analysis of Ba/F3 cells retrovirally transduced to express c-Kit receptors, phenylalanine substitution of c-Kit tyrosine residue 569 was shown to be associated with disruption of c-Kit-SHP-1 binding and induction of hyperproliferative responses to stem cell factor. Although phenylalanine substitution of c-Kit tyrosine residue 567 in the Ba/F3-c-Kit cells did not alter SHP-1 binding to c-Kit, the capacity of a second c-Kit-binding tyrosine phosphatase, SHP-2, to associate with c-Kit was markedly reduced, and the cells again showed hyperproliferative responses to stem cell factor. These data therefore identify SHP-1 binding to tyrosine 569 on c-Kit as an interaction pivotal to SHP-1 inhibitory effects on c-Kit signaling, but they indicate as well that cytosolic protein tyrosine phosphatases other than SHP-1 may also negatively regulate the coupling of c-Kit engagement to proliferation.

* Corresponding author. Mailing address: Life Sciences Division, Tunney's Pasture, Ottawa K1A 0L2, Canada. Phone: (613) 941-6594. Fax: (613) 941-8933. E-mail: Maya_Kozlowski{at}hc-sc.gc.ca.




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