REGULATION OF SMALL GTPASES BY THE CFES TYROSINE KINASE

Project: Research project

Project Details

Description

The proto-oncogene c-fes encodes a cytoplasmic protein-tyrosine kinase
that is expressed primarily in hematopoietic cells of granulocytic and
monocytic lineages. Transfection of the myeloid leukemia cell line
K-562 with c-fes causes growth suppression and differentiation,
suggesting that this kinase directly regulates myeloid development.
Recent studies show that transformation of fibroblasts with activated
homologs of c-Fes requires the activity of Ras, Rac and Cdc42 and
stimulates ERK and JNK activity, suggesting that these small G
protein/MAPK signaling pathways may mediate Fes-induced differentiation
of myeloid cells. Fes has also been shown to phosphorylate Bcr, Vav and
other regulatory proteins for the Ras and Rho families of small GTPases.
The broad goal of this project is to test the hypothesis that activation
of Ras and Rho family GTPases is essential for Fes-induced myeloid
differentiation. This hypothesis will be investigated with three
specific aims designed to answer the following questions: 1) Does Fes-
mediated tyrosine phosphorylation stimulate Bcr and Vav guanine
nucleotide exchange activity in vitro? 2) Do Bcr and Vav couple Fes to
small G protein signaling in living cells? 3) Does Fes-induced myeloid
differentiation depend upon activation of the Ras, Rac and Cdc42
signaling cascades? Results from these experiments will help elucidate
the intracellular signaling pathways downstream of Fes in myeloid
differentiation. Fes, and the components of its signaling pathway, may
ultimately provide drug targets for the differentiation therapy of
myeloid leukemia.
StatusFinished
Effective start/end date6/1/985/31/00

Funding

  • National Cancer Institute
  • National Cancer Institute

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