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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 132-138
The Shc adaptor protein forms interdependent
phosphotyrosine-mediated protein complexes in mast cells stimulated
with interleukin 3
Laura Velazquez,
Gerald D. Gish,
Peter van
der Geer,
Lorne Taylor,
Johanna Shulman, and
Tony Pawson
From the Programme in Molecular Biology and Cancer, Samuel Lunenfeld
Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
Department of Chemistry and Biochemistry, University of California, San
Diego, La Jolla, CA; PE SCIEX, Concord, Ontario, Canada; and the
Department of Molecular and Medical Genetics, University of Toronto,
Toronto, Ontario, Canada.
The Shc adaptor protein possesses 2 distinct phosphotyrosine (pTyr)
recognition modules the pTyr binding (PTB) domain and the Src homology
2 (SH2) domainand multiple potential sites for tyrosine (Tyr)
phosphorylation (Tyr residues 239, 240, and 317). On stimulation of
hematopoietic cells with interleukin 3 (IL-3), Shc becomes
phosphorylated and may therefore contribute to IL-3 signaling. We
investigated the interactions mediated by the Shc modular domains and
pTyr sites in IL-3-dependent IC2 premast cells. The Shc PTB domain,
rather than the SH2 domain, associated both in vitro and in vivo with
the Tyr-phosphorylated  subunit of the IL-3 receptor and with the
SH2-containing 5' inositol phosphatase (SHIP), and it recognized
specific NXXpY phosphopeptides from these binding partners. In
IL-3-stimulated mast cells, Shc phosphorylation occurred primarily on
Tyr239 and 317 and was dependent on a functional PTB domain.
Phosphorylated Tyr317, and to a lesser extent, Tyr239, bound the Grb2
adaptor and SHIP. Furthermore, a pTyr317 Shc phosphopeptide selectively
recognized Grb2, Sos1, SHIP, and the p85 subunit of phosphatidylinositol 3' kinase from mast cells, as characterized by mass spectrometry. These results indicate that Shc undergoes an
interdependent series of pTyr-mediated interactions in IL-3-stimulated mast cells, resulting in the recruitment of proteins that regulate the
Ras pathway and phospholipid metabolism.
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