The conditional expression of endogenous levels of oncogenic K-rasG12D allele in murine embryonic fibroblasts (MEF’s) induces enhanced proliferation and immortalization. Surprinsingly, K-rasG12D-expressing fibroblasts show attenuation of Ras effector pathways: Mitogen-activated protein kinase (MAPK) and PI3-Kinase/Akt. In order to identify downstream target of oncogenic K-rasG12D involved in the attenuation of canonical Ras effector signaling pathways, we have carried out analyses of gene expression by microarrays in MEF’s expressing oncogenic K-rasG12D versus wild-type MEF’s. Among all the genes identified, we chose to focus our attention on Sprouty-2 (Spry-2), a protein up-regulated in MEF’s expressing endogenous levels of K-rasG12D. Spry-2 is a negative regulator of receptor tyrosine kinases (RTKs) signaling and RAF signaling. Therefore, we are currently characterizing the role of Spry-2 in K-rasG12D mediated transformation, and whether Spry-2 is responsible for the attenuation of the MAPK pathway.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]