UV-radiation-induced internalization of the epidermal growth factor receptor requires distinct serine and tyrosine residues in the cytoplasmic carboxy-terminal domain.
The mechanism of UV-radiation-induced EGF receptor (EGFR) internalization remains to be established. In the present study, we found UV-radiation-mediated internalization of the EGFR to be dependent on the cytoplasmic carboxy-terminal region. UV radiation was unable to induce internalization of EGFR carboxy-terminal truncation mutants where all or four of the five major autophosphorylation sites were missing (963- and 1028-EGFR, respectively). Mutational removal of serine residues 1046, 1047, 1057 and 1142 within the carboxy-terminal receptor region was also sufficient to abolish UV-radiation-induced internalization of the EGFR. Furthermore, the UV-radiation-induced internalization was abrogated for an EGFR mutated in tyrosine 1045 (Y1045F), the major c-Cbl binding site. However, UV radiation did not induce phosphorylation at tyrosine 1045, in contrast to the prominent phosphorylation induced by EGF. Our results suggest a mechanism for UV-radiation-induced internalization of EGFR involving a conformational change that is dependent on structural elements formed by specific serine and tyrosine residues in the carboxy-terminal domain.
Oksvold
Morten P
MP
School of Surgery Pathology, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia. m.p.oksvold@labmed.uio.no
Thien
Christine B F
CB
Widerberg
Jannicke
J
Chantry
Andrew
A
Huitfeldt
Henrik S
HS
Langdon
Wallace Y
WY
D000595:Amino Acid Sequence; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism* / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011487:Protein Conformation; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays
D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D014443:Tyrosine; D012694:Serine; D066246:ErbB Receptors