AN INCOMPLETE PROGRAM OF CELLULAR TYROSINE PHOSPHORYLATIONS INDUCED BY KINASE-DEFECTIVE EPIDERMAL GROWTH-FACTOR RECEPTORS

Although signaling by the epidermal growth factor (EGF) receptor is th ought to be dependent on receptor tyrosine kinase activity, it is clea r that mitogen-activated protein (MAP) kinase can be activated by rece ptors lacking kinase activity, Since analysis of the signaling pathway s used by kinase-defective receptors could reveal otherwise masked cap abilities, we examined in detail the tyrosine phosphorylations and enz ymes of the MAP kinase pathway induced by kinase-defective EGF recepto rs, Following EGF stimulation of B82L cells expressing a kinase-defect ive EGF receptor mutant (K721M), we found that ERK2 and ERK1 MAP kinas es, as well as MEK1 and MEK2 were all activated, and SHC became promin ently tyrosine-phosphorylated. By contrast, kinase defective receptors failed to induce detectable phosphorylations of GAP (GTPase-activatin g protein), p62, JAK1, or P91STAT1, all of which were robustly phospho rylated by wild-type receptors, These data demonstrate that kinase def ective receptors induce several protein tyrosine phosphorylations, but that these represent only a subset of those seen with wild-type recep tors, This suggests that kinase-defective receptors activate a heterol ogous tyrosine kinase with a specificity different from the EGF recept or, We found that kinase-defective receptors induced ErbB2/c-Neu enzym atic activation and ErbB2/c-Neu binding to SHC at a level even greater than that induced by wild-type receptors, Thus, heterodimerization wi th and activation of endogenous ErbB2/c Neu is a possible mechanism by which kinase defective receptors stimulate the MAP kinase pathway.