REGULATION OF THE RAS TRANSFORMATION PATHWAY

Project: Research project

Description

The Ras oncoproteins play a critical role in cell growth and
differentiation, transducing signals from upstream protein tyrosine
kinases (PTKs) to the nuclear transcriptional machinery. In recent years,
considerable progress has been made in identifying additional proteins
that relay growth stimulatory signals down the "ras pathway". However,
interactions between existing proteins are only poorly understood, and it
is clear that further regulatory molecules remain to be identified. The
goal of this proposal is to characterize the mechanism(s) by which three
critical members of the Ras pathway, GAP (GTPase-activating protein), GDS
(guanine nucleotide dissociation stimulator), and GRB2 regulate Ras
activity and to identify novel molecular associations required for their
function. While pl20 GAP is clearly a negative regulator of ras function, its
putative role as a downstream target and effector of ras signaling remains
controversial. We have recently obtained evidence for such a role and have
narrowed this property down to a region that includes the SH3 domain. We
will further characterize the role of this region by isolation, deletion
and mutational analysis, and identify putative downstream effector(s) of
the Ras transformation pathway that interact with GAP-SH3. Recent biochemical and genetic evidence has implicated CDC25 homologs
(mCDC25, mSOS1 and 2) as activators of ras function. However, beyond their
function as stimulators of the GTP/GDP cycle, little is known about the
biological consequences of their interaction with ras proteins. Therefore,
we will establish the role of these ras GDSs in mediating normal and
oncogenic ras functions, and determine whether deregulated GDS activity
may cause transformation in the absence of ras mutations. Finally, recent studies have implicated GRB-2 as the critical link that
transmits the mitogenic signal from activated receptor PTKs to ras, and
acts to stimulate the SOS exchange factor. However, we have obtained
preliminary evidence that the role of GRB2 in intracellular signaling may
be more complex, and may involve interactions with proteins other than
receptor-PTKs. We have proposed studies to clarify these additional
functions of GRB2. Taken together, these studies will provide fundamental information on the
mechanisms of Ras activation and may identify additional components
involved in regulating the ras pathway.
StatusFinished
Effective start/end date6/1/945/31/99

Funding

  • National Institutes of Health: $109,022.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $77,505.00
  • National Institutes of Health: $22,437.00
  • National Institutes of Health

Fingerprint

GTPase-Activating Proteins
Guanine Nucleotides
ras GTPase-Activating Proteins
Proteins
Activator Appliances
Receptor Protein-Tyrosine Kinases
ras Proteins
src Homology Domains
Oncogene Proteins
Growth
Guanosine Triphosphate
Molecular Biology
Mutation
Protein-Tyrosine Kinases
Cell Differentiation

ASJC

  • Medicine(all)