Role of SHPTP2 in Mitogenic Signaling.
Annual rept. 30 Sep 95-29 Sep 96,
IOWA UNIV IOWA CITY
Pagination or Media Count:
UR INITIAL OBJECTIVES WERE TO DETERMINE THE ROLE OF SHPTP2 in the growth factor insulin and epidermal growth factor activation of Ras. During the past funding period, these studies have lead us to identify a novel pathway directly involved in the down-regulation or inactivation of Ras following growth factor stimulation. We have been able to demonstrate that the inactivation of Ras occurs due to either an uncoupling of SOS from Grb2 via insulin or an uncoupling of hc from Grb2-SOS via EGF due to a feedback serinethreonine phosphorylation of OS. We have also recently demonstrated that these events occurs by a MEK- dependent but ERK-independent kinase. In order to further examine this critical regulatory pathway in the control of Ras activation inactivation, we will identify the functional insulin and EGF stimulated SOS phosphorylation sites by deletion analysis and by site-directed mutagenesis. In parallel, we will perform PLC analysis to characterize and hopefully clone the specific kinase responsible or the functional phosphorylation of SOS. Finally, we will determine whether his phosphorylation is sufficient to account for the inactivation of Ras by performing in vitro dissociation studies and by expressing dominant-interfering mutants of the isolated SOS kinase.
- Medicine and Medical Research