Thefirst draft of the Human Genome Projectwas unveiled recently showing that up to 20% of the 30,000-40,000 genes areinvolved in signaling.  There aremore than 520 protein kinases and of these 58 have been identified as receptortyrosine kinases (RTKs) and 32 as cytosolic protein tyrosine kinases.

Proteintyrosine kinases function in a variety of cellularactivities, e.g. cell growth, cell cycle progression, differentiation,embryonic development, anti-apoptosis, cell motility and adhesion, genetranscription, angiogenesis, ion channels and the list goes on.

We study one of the RTKs. This is the receptor for CSF-1, which stands for Colony StimulatingFactor-1, alsoknown as M-CSF or Macrophage Colony Stimulating Factor. As the name implies,CSF-1 is a key growth factor for cells of the monocyte-macrophage lineage.  The CSF-1 receptor is in the samefamily as the PDGF, kit and flk/flt receptors. We use the CSF-1 receptor as amodel for studying the basic mechanisms underlying the control of cell growth(increase in cell size), proliferation (cell division) and survival (Fig.1).  Mutations and upregulatedexpression of RTKs are frequent in human cancers.  Moreover the pathways utilized by RTKs are oftenconstitutively active.  Hence bothRTKs and their downstream effectors are potential targets for anticancer drug therapy.

Our research program focuses on a basic understanding of the roles ofintracellular signaling pathways activated by the CSF-1R in hematopoietic cellculture models as well as primary bone marrow-derived macrophages.  We are interested in all pathways that contribute toCSF-1-mediated cell growth and survival.

Tyrosine kinases function in signaling cascades that comprise different classes of molecules: other tyrosine kinases, serine/threonine kinases, lipid kinases, adaptors and scaffolding molecules. We recently found that one of the scaffolding molecules working downstream of the CSF-1R, Gab2, is markedly upregulated when embryonic stem cells are induced to differentiate into neurons. Consistently, primary neural stem cells isolated from the subventricular zone of postnatal mice express high levels of Gab2, which persist in neurons.  These findings are very exciting. We now wish to understand the role of Gab2 and other members of this family (Gab1 and Gab3) in the central nervous system. Specifically, we would like to know if Gab proteins play a role in maintenance of the neural stem cell pool and neuronal specification, which receptors activate Gab proteins and which signaling pathways are modulated by these molecules.

Fig. 1



Src kinases