Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival

The RET tyrosine kinase is a functional receptor for neurotrophic ligands o f the glial cell line-derived neurotrophic factor (GDNF) family, Loss of fu nction of RET Is associated with congenital megacolon or Hirschsprung's dis ease, whereas germ-line point mutations causing RET activation are responsi ble for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial med ullary thyroid carcinoma) syndromes, Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochrom ocytoma PC12 cells upon growth factor withdrawal, Moreover,,ve show that th e RET-MEN2A-mediated survival depends on signals transduced by the phosphoi nositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascad es. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subu nit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activa tion, PI3K recruitment and Akt activation as well as MAPK activation depend on RET-MEN2A tyrosine residue 1062, As a result, tyrosine 1062 of RET-MEN2 A is essential for RET-MEN2A-mediated survival of PC12 cells cultured in gr owth factor-depleted media.