c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription.
We have previously demonstrated that cellular stimulation with GH results in the formation of a multiprotein signaling complex. One component of this multiprotein signaling complex is the adapter molecule c-Cbl. Here we have examined the role of c-Cbl in the mechanism of GH signal transduction. Forced expression of c-Cbl in NIH3T3 cells did not alter GH-stimulated Janus kinase 2 tyrosine phosphorylation nor GH-stimulated p44/42 MAPK activation and consequent Elk-1- mediated transcription. c-Cbl overexpression did, however, result in enhanced and prolonged GH-stimulated activation of phosphatidylinositol 3-kinase. Forced expression of c-Cbl did not affect GH-stimulated STAT5 tyrosine phosphorylation, nuclear translocation, nor binding to DNA but markedly abrogated GH-stimulated STAT5-mediated transactivation. c-Cbl overexpression resulted in increased ubiquitination and proteosomal degradation of STAT5 and increased degradation of GH-stimulated tyrosine phosphorylated STAT5. Cellular pretreatment with the proteosomal inhibitor MG132 reversed the effect of c-Cbl overexpression with prolonged duration of GH-stimulated STAT5 tyrosine phosphorylation and restoration of STAT5-mediated transcription. Thus, c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription by direction of STAT5 for proteosomal degradation.
Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609.
Eyleen L K
EL
Goh
Tao
T
Zhu
Wan-Ying
WY
Leong
Peter E
PE
Lobie
D016475:3T3 Cells; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D019382:Human Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D053614:Janus Kinase 2; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011986:Receptors, Somatotropin / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007976:Leupeptins; D008894:Milk Proteins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D025801:Ubiquitin; D019382:Human Growth Hormone; D019000:Phosphotyrosine; D004247:DNA; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C067419:CBL protein, human; C493849:Cbl protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde