REGULATION OF SMALL GTPASES BY THE CFES TYROSINE KINASE

Project: Research projectPostdoctoral Individual National Research Service Award

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.
StatusActive
Effective start/end date11/27/98 → …

Funding

  • National Institutes of Health: $30,583.00
  • National Institutes of Health

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Monomeric GTP-Binding Proteins
Protein-Tyrosine Kinases
Myeloid Leukemia
Myeloid Cells
ras Proteins
rho GTP-Binding Proteins
Guanine Nucleotides
Proto-Oncogenes
Transfection
Tyrosine
Phosphotransferases
Fibroblasts
Phosphorylation
Cell Line
Growth
Pharmaceutical Preparations
Therapeutics