title: Jak2 is a negative regulator of ubiquitin-dependent endocytosis of the growth hormone receptor.
abstract: BACKGROUND
  Length and intensity of signal transduction via cytokine receptors is precisely regulated. Degradation of certain cytokine receptors is mediated by the ubiquitin ligase SCF(βTrCP). In several instances, Janus kinase (Jak) family members can stabilise their cognate cytokine receptors at the cell surface.
  
  
  RESULTS
  In this study we show in Hek293 cells that Jak2 binding to the growth hormone receptor prevents endocytosis in a non-catalytic manner. Following receptor activation, the detachment of phosphorylated Jak2 induces down-regulation of the growth hormone receptor by SCF(βTrCP). Using γ2A human fibroblast cells we show that both growth hormone-induced and constitutive growth hormone receptor endocytosis depend on the same factors, strongly suggesting that the modes of endocytosis are identical. Different Jak2 RNA levels in HepG2, IM9 and Hek293 cells indicate the importance of cellular concentration on growth hormone receptor function. Both Jak2 and βTrCP bind to neighbouring linear motifs in the growth hormone receptor tail without the requirement of modifications, indicating that growth hormone sensitivity is regulated by the cellular level of non-committed Jak2.
  
  
  CONCLUSIONS
  As signal transduction of many cytokine receptors depends on Jak2, the study suggests an integrative role of Jak2 in cytokine responses based on its enzyme activity as well as its stabilising properties towards the receptors.
authors.affiliation: Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: Putters
authors.forename: Ana C
authors.initials: AC
authors.lastname: da Silva Almeida
authors.forename: Peter
authors.initials: P
authors.lastname: van Kerkhof
authors.forename: Agnes G S H
authors.initials: AG
authors.lastname: van Rossum
authors.forename: Ana
authors.initials: A
authors.lastname: Gracanin
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Strous
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011817:Rabbits; D011986:Receptors, Somatotropin / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D011986:Receptors, Somatotropin; D025801:Ubiquitin; D019382:Human Growth Hormone; D044843:SKP Cullin F-Box Protein Ligases; D053614:Janus Kinase 2