title: Dimerization drives EGFR endocytosis through two sets of compatible endocytic codes.
abstract: We have shown previously that epidermal growth factor (EGF) receptor (EGFR) endocytosis is controlled by EGFR dimerization. However, it is not clear how the dimerization drives receptor internalization. We propose that EGFR endocytosis is driven by dimerization, bringing two sets of endocytic codes, one contained in each receptor monomer, in close proximity. Here, we tested this hypothesis by generating specific homo- or hetero-dimers of various receptors and their mutants. We show that ErbB2 and ErbB3 homodimers are endocytosis deficient owing to the lack of endocytic codes. Interestingly, EGFR-ErbB2 or EGFR-ErbB3 heterodimers are also endocytosis deficient. Moreover, the heterodimer of EGFR and the endocytosis-deficient mutant EGFRΔ1005-1017 is also impaired in endocytosis. These results indicate that two sets of endocytic codes are required for receptor endocytosis. We found that an EGFR-PDGFRβ heterodimer is endocytosis deficient, although both EGFR and PDGFRβ homodimers are endocytosis-competent, indicating that two compatible sets of endocytic codes are required. Finally, we found that to mediate the endocytosis of the receptor dimer, the two sets of compatible endocytic codes, one contained in each receptor molecule, have to be spatially coordinated.
authors.affiliation: The Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada zhixiang.wang@ualberta.ca.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D020797:Receptor, Platelet-Derived Growth Factor beta; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Dimerization; Dual endocytic codes; EGF receptor; Endocytosis