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Molecular and Cellular Biology, June 2006, p. 4149-4160, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01932-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

T-Cell Protein Tyrosine Phosphatase (Tcptp) Is a Negative Regulator of Colony-Stimulating Factor 1 Signaling and Macrophage Differentiation

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Department of Medical Biophysics, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada,¹ The McGill Cancer Centre, Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada,² The Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, B2-152, P.O. Box 19024, Seattle, Washington 98109-1024,³ and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461⁴

Received 3 October 2005/ Returned for modification 15 November 2005/ Accepted 4 March 2006

Mice null for the T-cell protein tyrosine phosphatase (Tcptp^–/–) die shortly after birth due to complications arising from the development of a systemic inflammatory disease. It was originally reported that Tcptp^–/– mice have increased numbers of macrophages in the spleen; however, the mechanism underlying the aberrant growth and differentiation of macrophages in Tcptp^–/– mice is not known. We have identified Tcptp as an important regulator of colony-stimulating factor 1 (CSF-1) signaling and mononuclear phagocyte development. The number of CSF-1-dependent CFU is increased in Tcptp^–/– bone marrow. Tcptp^–/– mice also have increased numbers of granulocyte-macrophage precursors (GMP), and these Tcptp^–/– GMP yield more macrophage colonies in response to CSF-1 relative to wild-type cells. Furthermore, we have identified the CSF-1 receptor (CSF-1R) as a physiological target of Tcptp through substrate-trapping experiments and its hyperphosphorylation in Tcptp^–/– macrophages. Tcptp^–/– macrophages also have increased tyrosine phosphorylation and recruitment of a Grb2/Gab2/Shp2 complex to the CSF-1R and enhanced activation of Erk after CSF-1 stimulation, which are important molecular events in CSF-1-induced differentiation. These data implicate Tcptp as a critical regulator of CSF-1 signaling and mononuclear phagocyte development in hematopoiesis.

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