RECEPTOR BIOLOGY EGFR with Sugar on Top

Abstract:

An epidermal growth factor receptor (EGFR) mutant (EGFRvIII/EGFR) harboring a large deletion of the EGFR extracellular domain is frequently found in several types of cancer. The kinase activity in the mutant no longer depends on EGF binding, and thus, the kinase is constitutively active but weaker. Fernandes et al. found that, in contrast to previous reports, the kinase activity of the mutant is at least as active as wild-type (wt) EGFR, and they may have uncovered a mechanism for the constitutive activation of EGFR. Both wt EGFR from EGF-treated cells and EGFR were immunoprecipitated with an antibody that specifically recognizes the catalytically active form of the receptor. Phosphopeptide mapping revealed that the same tyrosine residues were phosphorylated in wt and EGFR, and to similar stoichiometric levels. In the absence of EGF, EGFR but not wt EGFR formed activated dimers. Fernandes et al. found that glycosylation was also important for mediating an active conformation and consequent EGFR kinase activity. But is glycosylation continuously required for kinase activity or does it simply allow formation of a stable active conformation then become dispensable? The authors showed that the function of glycosylation is to permit the proper conformation of each subunit in the dimer; deglycosylation of active EGFR dimers did not affect their kinase activity, nor did the dimers dissociate. Tunicamycin-treated EGFR (prevented from undergoing de novo glycosylation) was unable to form dimers, suggesting that glycosylation is required for the constitutive activation of EGFR.

H. Fernandes, S. Cohen, S. Bishayee, Glycosylation-induced conformational modification positively regulates receptor-receptor association: A study with an aberrant epidermal growth factor receptor (EGFRvIII/EGFR) expressed in cancer cells. J. Biol. Chem. 276, 5375-5383 (2001). [Abstract] [Full Text]