Verbatim): The M-CSF receptor, Fms, is a tyrosine kinase growth factor receptor expressed primarily in the monocyte-macrophage lineage of hematopoietic cell development. The molecular signals transmitted within susceptible cells by the activated Fms contribute to the development of cells toward mature macrophages. Homologues of Fms are expressed throughout the various stages of hematopoiesis where they regulate the development of distinct lineages and/or phases of progenitor cell growth and maturation. For example, Kit is expressed in progenitor cells and mature mast cells, Flt3 is broadly expressed in progenitor cell populations, and Flt I (also called KDR) may be expressed in stem cells. Thus, Fms may be considered the prototypical receptor for investigations of the signaling mechanism by these other tyrosine kinase growth factor receptors. The analyses of Fms signaling are more amenable to experimentation, and the results may be mechanistically relevant to the other receptors. We have been interested in the M-CSF-induced molecular signals that contribute to growth and differentiation, and how , both signals are integrated and regulated by Fms. Recent data indicate that multifunctional scaffolding proteins link the receptor to downstream signals. These proteins are called Gab-family members (exemplified by Gabl, Gab2, and Gab3), and the research results from the Drosophilahomologue, DOS, suggests they are necessary for development. We propose to investigate the molecular role of these proteins in Fms signaling using both biochemical analyses of protein signaling interactions in cell lines and genetic studies in Gab-knockout mice. These studies will be extended to look for additional Gab-family members in early stem/progenitor cells. Overall, the results of these experiments will describe new signaling mechanisms that may be useful for understanding the normal and abnormal development of blood cells and their diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Brocqueville, Guillaume; Chmelar, Renee S; Bauderlique-Le Roy, Hélène et al. (2016) s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells. Oncotarget 7:29228-44
Bai, Lixia; Rohrschneider, Larry R (2010) s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue. Genes Dev 24:1882-92
Simoncic, Paul D; Bourdeau, Annie; Lee-Loy, Ailsa et al. (2006) T-cell protein tyrosine phosphatase (Tcptp) is a negative regulator of colony-stimulating factor 1 signaling and macrophage differentiation. Mol Cell Biol 26:4149-60
Rohrschneider, Larry R; Custodio, Joseph M; Anderson, Tamara A et al. (2005) The intron 5/6 promoter region of the ship1 gene regulates expression in stem/progenitor cells of the mouse embryo. Dev Biol 283:503-21
Seiffert, Martina; Custodio, Joseph M; Wolf, Ingrid et al. (2003) Gab3-deficient mice exhibit normal development and hematopoiesis and are immunocompetent. Mol Cell Biol 23:2415-24
Wolf, Ingrid; Jenkins, Brendan J; Liu, Yan et al. (2002) Gab3, a new DOS/Gab family member, facilitates macrophage differentiation. Mol Cell Biol 22:231-44
Wolf, I; Lucas, D M; Algate, P A et al. (2000) Cloning of the genomic locus of mouse SH2 containing inositol 5-phosphatase (SHIP) and a novel 110-kDa splice isoform, SHIPdelta. Genomics 69:104-12
Bourette, R P; Rohrschneider, L R (2000) Early events in M-CSF receptor signaling. Growth Factors 17:155-66
Wolf, I; Rohrschneider, L R (1999) Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase Flt3. J Biol Chem 274:21478-84
Timms, J F; Carlberg, K; Gu, H et al. (1998) Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. Mol Cell Biol 18:3838-50

Showing the most recent 10 out of 33 publications