title: Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation.
abstract: Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Bharat
authors.initials: B
authors.lastname: Joshi
authors.forename: Michele
authors.initials: M
authors.lastname: Bastiani
authors.forename: Scott S
authors.initials: SS
authors.lastname: Strugnell
authors.forename: Cecile
authors.initials: C
authors.lastname: Boscher
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Nabi
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021941:Caveolae / Q000502:physiology*; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D014443:Tyrosine