title: Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta.
abstract: Epithelial-mesenchymal transformation (EMT) and the resulting induction of cell motility are essential components of tissue remodeling during embryonic development and wound repair, as well as tumor progression to an invasive metastatic phenotype. Paxillin, a multi-domain adaptor and phosphoprotein has previously been implicated in integrin signaling and cell motility. In this report we characterize a novel paxillin gene product, paxillin delta, generated from an evolutionarily conserved internal translation initiation site within the full-length paxillin mRNA. Paxillin delta, which lacks the key phosphorylation sites Y31 and Y118 as well as the ILK and actopaxin binding LD1 motif, exhibits a restricted distribution to epithelial cell types and is downregulated during TGF-beta1-induced EMT of normal murine mammary gland (NMuMG) epithelial cells. Interestingly, Hic-5, a paxillin superfamily member, exhibits a reciprocal protein expression profile to paxillin delta. In addition, paxillin delta expression is maintained following NMuMG differentiation in a 3D collagen I gel while other focal adhesion components are downregulated. Paxillin delta protein expression coincided with reduced paxillin tyrosine phosphorylation in NMuMG cells and paxillin delta overexpression in CHO.K1 cells inhibited adhesion-mediated tyrosine phosphorylation of paxillin. Forced expression of paxillin delta in NMuMG cells suppressed cell migration whereas Hic-5 overexpression stimulated motility. Together our data support a role for paxillin delta as a naturally occurring functional antagonist of paxillin signaling potentially through suppression of a Crk-mediated pathway during processes associated with cell migration.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tumbarello
authors.forename: Michael C
authors.initials: MC
authors.lastname: Brown
authors.forename: Sara E
authors.initials: SE
authors.lastname: Hetey
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D022001:Focal Adhesions; D015870:Gene Expression; D060588:LIM Domain Proteins; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051419:Paxillin / Q000737:chemistry / Q000145:classification* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016596:Vinculin
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D051419:Paxillin; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins; C090090:Tgfb1i1 protein, mouse; D016212:Transforming Growth Factor beta; D016596:Vinculin; D003094:Collagen