J. Baulida et al., ALL ERBB RECEPTORS OTHER THAN THE EPIDERMAL GROWTH-FACTOR RECEPTOR ARE ENDOCYTOSIS IMPAIRED, The Journal of biological chemistry, 271(9), 1996, pp. 5251-5257
Four transmembrane tyrosine kinases constitute the ErbB receptor famil
y: the epidermal growth factor (EGF) receptor, ErbB-2, ErbB-3, and Erb
B-4. We have measured the endocytic capacities of all four members of
the EGF receptor family, including ErbB-3 and ErbB-4, which have not b
een described previously. EGF-responsive chimeric receptors containing
the EGF receptor extracellular domain and different ErbB cytoplasmic
domains (EGFR/ErbB) have been employed. The capacity of these growth f
actor-receptor complexes to mediate I-125-EGF internalization, recepto
r down-regulation, receptor degradation, and receptor co-immunoprecipi
tation with AP-2 was assayed. In contrast to the EGF receptor, all EGF
R/ErbB receptors show impaired ligand-induced rapid internalization, d
own-regulation, degradation, and AP-2 association. Also, we have analy
zed the heregulin-responsive wild-type ErbB-4 receptor, which does not
mediate the rapid internalization of I-125-heregulin, demonstrates no
heregulin-regulated receptor degradation, and fails to form associati
on complexes with AP-2. Despite the substantial differences in ligand-
induced receptor trafficking between the EGF and ErbB-4 receptors, EGF
and heregulin have equivalent capacities to stimulate DNA synthesis i
n quiescent cells. These results show that the ligand-dependent down-r
egulation mechanism of the EGF receptor, surprisingly, is not a proper
ty of any other known ErbB receptor family member. Since endocytosis i
s thought to be an attenuation mechanism for growth factor-receptor co
mplexes, these data imply that substantial differences in attenuation
mechanisms exist within one family of structurally related receptors.