Threonine phosphorylation diverts internalized epidermal growth factor receptors from a degradative pathway to the recycling endosome.
Transregulation of the epidermal growth factor receptor (EGFR) by protein kinase C (PKC) serves as a model for heterologous desensitization of receptor tyrosine kinases, but the underlying mechanism remained unknown. By using c-Cbl-induced ubiquitination of EGFR as a marker for transfer from early to late endosomes, we provide evidence that PKC can inhibit this process. In parallel, receptor down-regulation and degradation are significantly reduced. The inhibitory effects of PKC are mediated by a single threonine residue (threonine 654) of EGFR, which serves as a major PKC phosphorylation site. Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surface. In conclusion, by sorting EGFR to the recycling endosome, heterologous desensitization restrains ligand-induced down-regulation of EGFR.
Bao
J
J
Departments of Biological Regulation and Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Alroy
I
I
Waterman
H
H
Schejter
E D
ED
Brodie
C
C
Gruenberg
J
J
Yarden
Y
Y
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D015536:Down-Regulation; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008024:Ligands; D008985:Monensin / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D013329:Structure-Activity Relationship; D013912:Threonine / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism
D007476:Ionophores; D008024:Ligands; D011518:Proto-Oncogene Proteins; D014452:Ubiquitins; D013912:Threonine; D008985:Monensin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D011493:Protein Kinase C