Toshiyuki Araki, PhD

My research is primarily focused on the mechanism how the RAS/ERK pathways are regulated in growth factor signaling. The RAS/ERK pathway regulates multiple cellular processes, including migration, growth, proliferation, metabolism, and programmed cell death. Not surprisingly, abnormalities in this pathway contribute to multiple malignancies as well as other disorders. Optimal RAS activation in response to receptor tyrosine kinase (RTK) stimulation typically requires the protein-tyrosine phosphatase SHP2, encoded by PTPN11. Shp2 contains two SH2 domains at N-terminus, tyrosine phosphatase domain, several tyrosine phosphorylation sites.

Multiple of studies show that the disruption or mutations in the components of RAS/ERK pathway cause embryonic lethal due to abnormal placental formation and functions. As expected, our earlier study show that Shp2 knockout embryos die at peri-implantation presumably due to the lack of Ras/Erk activation by FGF4 in trophoblast stem cells. Our recent structure-function analysis in mice unexpectedly reveals that SHP2 catalytic activity is dispensable for early mouse development and RAS activation by EGFR and FGFR. We take advantage of a combination of genetic, pharmacological, biochemical and proteomics approaches to address how optimal RAS activation is regulated by each sub-domain of SHP2.