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Volume 272, Number 25, Issue of June 20, 1997 pp. 15943-15950
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Characterization of a Novel Tyrosine Phosphorylated 100-kDa Protein That Binds to SHP-2 and Phosphatidylinositol 3-Kinase in Myeloid Cells

(Received for publication, February 6, 1997, and in revised form, April 17, 1997)

From the Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109-1024

Fms is a tyrosine kinase-containing receptor for macrophage colony-stimulating factor (M-CSF) that regulates survival, growth, and differentiation of cells along the monocyte/macrophage lineage. M-CSF stimulation of murine myeloid FDC-P1 cells expressing Fms resulted in the tyrosine phosphorylation of a number of signal transduction proteins, including an unidentified 100-kDa protein. This 100-kDa protein associated with the tyrosine phosphatase SHP-2 but not with the related phosphatase SHP-1. The kinetics of tyrosine phosphorylation of p100 and SHP-2 suggest that p100 may be a direct substrate of SHP-2. p100 bound directly to the SH2 domains of both SHP-2 and the p85 subunit of phosphatidylinositol 3-kinase. The 100-kDa protein did not appear to bind directly to Fms, Ship, Cbl, Shc, or Grb2, although all of these proteins were coimmunoprecipitated with p85 after M-CSF stimulation. Association of p100 with SHP-2 and p85 did not require the major autophosphorylation sites on Fms nor binding of p85 to Fms. A tyrosine phosphorylated protein of 100 kDa also coprecipitated with SHP-2 from several other myeloid cell lines after M-CSF stimulation but was not seen in immunoprecipitates from Rat2 fibroblasts expressing Fms. Stimulation of FDC-P1 cells with additional cytokines also resulted in coprecipitation of a 100-kDa protein with SHP-2. p100 may therefore be a common component of the signaling pathways of cytokine receptors in myeloid cells.

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