title: Mig-6 participates in the regulation of cell senescence and retinoblastoma protein phosphorylation.
abstract: Mitogen-inducible gene-6 (Mig-6) is a cytosolic multiadaptor protein that is best known for its role as a negative feedback regulator of epidermal growth factor receptor (EGFR) mediated signalling. Alternative roles of Mig-6 are becoming increasingly recognised. Consistently with this, Mig-6 was demonstrated to be involved in a broad spectrum of cellular events including tumour suppression which may include the induction of cellular senescence. Here, we investigated the mechanisms of Mig-6 induced premature cell senescence. Endogenous Mig-6 is poorly expressed in young fibroblasts, whilst its expression rises in cells presenting with typical features of senescence. Overexpression of Mig-6 is sufficient to trigger premature cellular senescence of early passage diploid lung fibroblasts (WI-38). Interestingly, Mig-6 overexpression reduced retinoblastoma protein (pRb) phosphorylation at the inactivating Ser249/Thr252 sites. We also found that phosphorylation of these sites in pRb is increased in the presence of the B-Raf V600E oncogenic mutation. We further show that Mig-6 overexpression reduces B-Raf V600E mediated pRb inactivation and preserves pRb function.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: malgorzata.milewska@ucd.ie.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milewska
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: walter.kolch@ucd.ie.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: B-Raf V600E; Cellular senescence; Human diploid lung fibroblasts; Mig-6; Phospho-retinoblastoma (Ser249/Thr252)