Most of our recent growth regulation research has been concerned with the ras oncogene and its positive regulators, the Ras-specific guanine nucleotide exchange factors (Ras-GNEFs). These molecules play a key role in signal transduction and ras is mutationally activated in many human and animal tumors. The analysis of two closely related, widely expressed Ras-GNEFs, sos1 and sos2, has identified important differences in the stability of their encoded proteins and in the duration of their signaling properties. The Sos2 protein carries out long-term signaling less efficiently than Sos1 to a degree that physiologic levels of Sos2 cannot support transformation by oncoproteins such as tyrosine kinases, which rely on Sos-dependent activation of Ras for their transforming activity. In addition, the Sos2 protein is a physiologic substrate for degradation by the ubiquitin-proteasome system, while Sos1 is not subject to such regulation. Other studies on signaling through Sos indicate that coordinate signals at the N-terminus and C-terminus of the protein are required for its activation. We are also studying GRF1 and GRF2, two closely related brain-specific Ras-GNEFs, that are activated by calcium. We have found that the calcium-dependent activation of GRF stimulates Raf via two signals, one that is Ras-dependent and another that is Ras-independent. Also, GRF1 and GRF2 form homo- and hetero-dimers through their Dbl domains. Dimerization may be required for propagating the Ras-independent signal from GRF that stimulates Raf. Further studies are planned to elucidate the mechanisms underlying the regulation of Sos and GRF signaling.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008905-19
Application #
6433127
Study Section
(LCO)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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