Description of Lab Projects

Cellular responses to activation of growth factor receptors is dictated by the repertoire of signaling molecules present within a given cell type.  Weidentified a novel mechanism utilized by the CSF-1R for activating thephosphatidylinositol 3-kinase (PI3K)/Akt survival pathway in the 32D myeloidcell line (Fig. 1).  Unlike thepreviously described pathway involving direct CSF-1R:PI3K binding, this novelmechanism is activated by a deletion mutant of CSF-1R (DKI) that cannot bind PI3K.  Using both pharmacological and genetic approaches, wedetermined that the novel pathway involves a CSF-1R-Src-Gab2-PI3K link.  Src family kinases are cytosolictyrosine kinases whereas Gab2 is a recently identified docking/scaffoldingmolecule that may play a particularly important role in hematopoieticsystems.  Current research focus isto further delineate the roles of Src and Gab2 in mediating CSF-1 signalsnecessary for growth and survival. Additional recent studies from our lab have revealed that the DKI mutant is mitogenically defective andundergoes a novel form of cell death that appears to be largely independent ofcaspases and mitochondrial dysfunction. Complementationwith constitutively active downstream signaling molecules in combination with geneexpression microarrayprofiling are in progress to further elucidate the mechanisms of cell growthand death.

Recent exciting results in the lab point to an essential role for Gab2 in maintaining neural stem cell proliferation (self-renewal). Since a multitude of receptor tyrosine kinases are found in neural stem cells and their progeny (neurons, astrocytes and oligodendrocytes), this has significant implication.

Further description of individual projects is provided inthe individual links.

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Lee and States, MCB 20:6779,2000

Fig. 1

Src kinases