title: Ubc13 and COOH terminus of Hsp70-interacting protein (CHIP) are required for growth hormone receptor endocytosis.
abstract: Growth hormone receptor (GHR) endocytosis is a highly regulated process that depends on the binding and activity of the multimeric ubiquitin ligase, SCF(βTrCP) (Skp Cullin F-box). Despite a specific interaction between β-transducin repeat-containing protein (βTrCP) and the GHR, and a strict requirement for ubiquitination activity, the receptor is not an obligatory target for SCF(βTrCP)-directed Lys(48) polyubiquitination. We now show that also Lys(63)-linked ubiquitin chain formation is required for GHR endocytosis. We identified both the ubiquitin-conjugating enzyme Ubc13 and the ubiquitin ligase COOH terminus of Hsp70 interacting protein (CHIP) as being connected to this process. Ubc13 activity and its interaction with CHIP precede endocytosis of GHR. In addition to βTrCP, CHIP interacts specifically with the cytosolic tails of the dimeric GHR, identifying both Ubc13 and CHIP as novel factors in the regulation of cell surface availability of GHR.
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht and Institute of Biomembranes, 3584 CX Utrecht, The Netherlands.
authors.forename: Johan A
authors.initials: JA
authors.lastname: Slotman
authors.forename: Ana C
authors.initials: AC
authors.lastname: da Silva Almeida
authors.forename: Gerco C
authors.initials: GC
authors.lastname: Hassink
authors.forename: Robert H A
authors.initials: RH
authors.lastname: van de Ven
authors.forename: Peter
authors.initials: P
authors.lastname: van Kerkhof
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Kuiken
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Strous
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004705:Endocytosis; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D055503:Protein Multimerization; D034622:RNA Interference; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011986:Receptors, Somatotropin; D044844:beta-Transducin Repeat-Containing Proteins; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine