Jd. Wright et al., AN INCOMPLETE PROGRAM OF CELLULAR TYROSINE PHOSPHORYLATIONS INDUCED BY KINASE-DEFECTIVE EPIDERMAL GROWTH-FACTOR RECEPTORS, The Journal of biological chemistry, 270(20), 1995, pp. 12085-12093
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.