title: LAR protein tyrosine phosphatase regulates focal adhesions through CDK1.
abstract: Focal adhesions are complex multi-molecular structures that link the actin cytoskeleton to the extracellular matrix through integrin adhesion receptors and play a key role in regulation of many cellular functions. LAR (also known as PTPRF) is a receptor protein tyrosine phosphatase that regulates PDGF signalling and localises to focal adhesions. We have observed that loss of LAR phosphatase activity in mouse embryonic fibroblasts results in reduced numbers of focal adhesions and decreased adhesion to fibronectin. To understand how LAR regulates cell adhesion we used phosphoproteomic data, comparing global phosphorylation events in wild-type and LAR phosphatase-deficient cells, to analyse differential kinase activity. Kinase prediction analysis of LAR-regulated phosphosites identified a node of cytoskeleton- and adhesion-related proteins centred on cyclin-dependent kinase-1 (CDK1). We found that loss of LAR activity resulted in reduced activity of CDK1, and that CDK1 activity was required for LAR-mediated focal adhesion complex formation. We also established that LAR regulates CDK1 activity through c-Abl and Akt family proteins. In summary, we have identified a new role for a receptor protein tyrosine phosphatase in regulating CDK1 activity and hence cell adhesion to the extracellular matrix.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Adil R
authors.identifier: 0000-0003-2163-4910
authors.initials: AR
authors.lastname: Sarhan
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Trushar R
authors.identifier: 0000-0003-0627-2923
authors.initials: TR
authors.lastname: Patel
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Alana R
authors.initials: AR
authors.lastname: Cowell
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tomlinson
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Carina
authors.initials: C
authors.lastname: Hellberg
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: John K
authors.identifier: 0000-0003-4886-4070
authors.initials: JK
authors.lastname: Heath
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK n.a.hotchin@bham.ac.uk d.l.cunningham@bham.ac.uk.
authors.forename: Debbie L
authors.identifier: 0000-0001-7776-690X
authors.initials: DL
authors.lastname: Cunningham
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK n.a.hotchin@bham.ac.uk d.l.cunningham@bham.ac.uk.
authors.forename: Neil A
authors.identifier: 0000-0002-1844-7607
authors.initials: NA
authors.lastname: Hotchin
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005353:Fibronectins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: CDK1; Cell adhesion; Focal adhesions; LAR phosphatase; PTPRF