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Molecular and Cellular Biology, May 2001, p. 3047-3056, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3047-3056.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Scaffolding Protein Gab2 Mediates Differentiation Signaling Downstream of Fms Receptor Tyrosine Kinase

Yan Liu,* Brendan Jenkins,dagger Jung Lim Shin, and Larry R. Rohrschneider

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Received 24 August 2000/Returned for modification 12 October 2000/Accepted 7 February 2001

Fms is the receptor for macrophage colony-stimulating factor (M-CSF) and contains intrinsic tyrosine kinase activity. Expression of exogenous Fms in a murine myeloid progenitor cell line, FDC-P1 (FD-Fms), results in M-CSF-dependent growth and macrophage differentiation. Previously, we described a 100-kDa protein that was tyrosine phosphorylated upon M-CSF stimulation of FD-Fms cells. In this report, we identify this 100-kDa protein as the recently cloned scaffolding protein Gab2, and we demonstrate that Gab2 associates with several molecules involved in M-CSF signaling, including Grb2, SHP2, the p85 subunit of phosphatidylinositol 3'-kinase, SHIP, and SHC. Tyrosine phosphorylation of Gab2 in response to M-CSF requires the kinase activity of Fms, but not that of Src. Overexpression of Gab2 in FD-Fms cells enhanced both mitogen-activated protein kinase (MAPK) activity and macrophage differentiation, but reduced proliferation, in response to M-CSF. In contrast, a mutant of Gab2 that is unable to bind SHP2 did not potentiate MAPK activity. Furthermore, overexpression of this mutant in FD-Fms cells inhibited macrophage differentiation and resulted in a concomitant increase in growth potential in response to M-CSF. These data indicate that Gab2 is involved in the activation of the MAPK pathway and that the interaction between Gab2 and SHP2 is essential for the differentiation signal triggered by M-CSF.

* Corresponding author. Mailing address: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, B2-152, P.O. Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-4437. Fax: (206) 667-3308. E-mail: yliu{at}fhcrc.org.

dagger Present address: Molecular Biology Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia.

Molecular and Cellular Biology, May 2001, p. 3047-3056, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3047-3056.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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