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Mol. Cell. Biol. 22 (1): 231-244

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Gab3, a New DOS/Gab Family Member, Facilitates Macrophage Differentiation

Ingrid Wolf,1 Brendan J. Jenkins,1,{dagger} Yan Liu,1 Martina Seiffert,1 Joseph M. Custodio,1 Paul Young,2,{ddagger} and Larry R. Rohrschneider1*

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024,1 Human Genome Sciences, Inc., Rockville, Maryland 208502

Received for publication 6 August 2001. Accepted for publication 3 October 2001.

Abstract: Using the FDC-P1 cell line expressing the exogenous macrophage colony-stimulating factor (M-CSF) receptor, Fms, we have analyzed the role of a new mammalian DOS/Gab-related signaling protein, called Gab3, in macrophage cell development of the mouse. Gab3 contains an amino-terminal pleckstrin homology domain, multiple potential sites for tyrosine phosphorylation and SH2 domain binding, and two major polyproline motifs potentially interacting with SH3 domains. Among the growing family of Gab proteins, Gab3 exhibits a unique and overlapping pattern of expression in tissues of the mouse compared with Gab1 and Gab2. Gab3 is more restricted to the hematopoietic tissues such as spleen and thymus but is detectable at progressively lower levels within heart, kidney, uterus, and brain. Like Gab2, Gab3 is tyrosine phosphorylated after M-CSF receptor stimulation and associates transiently with the SH2 domain-containing proteins p85 and SHP2. Overexpression of exogenous Gab3 in FD-Fms cells dramatically accelerates macrophage differentiation upon M-CSF stimulation. Unlike Gab2, which shows a constant mRNA expression level after M-CSF stimulation, Gab3 expression is initially absent or low in abundance in FD cells expressing the wild-type Fms, but Gab3 mRNA levels are increased upon M-CSF stimulation. Moreover, M-CSF stimulation of FD-FmsY807F cells (which grow but do not differentiate) fails to increase Gab3 expression. These results suggest that Gab3 is important for macrophage differentiation and that differentiation requires the early phosphorylation of Gab2 followed by induction and subsequent phosphorylation of Gab3.

* 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) 667-4441. Fax: (206) 667-3308. E-mail: lrohrsch@fhcrc.org.

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

{ddagger} Present address: Avalon Pharmaceuticals, Gaithersburg, MD 20878.

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