title: Integrin-specific signaling pathways controlling focal adhesion formation and cell migration.
abstract: The fibronectin (FN)-binding integrins alpha4beta1 and alpha5beta1 confer different cell adhesive properties, particularly with respect to focal adhesion formation and migration. After analyses of alpha4+/alpha5+ A375-SM melanoma cell adhesion to fragments of FN that interact selectively with alpha4beta1 and alpha5beta1, we now report two differences in the signals transduced by each receptor that underpin their specific adhesive properties. First, alpha5beta1 and alpha4beta1 have a differential requirement for cell surface proteoglycan engagement for focal adhesion formation and migration; alpha5beta1 requires a proteoglycan coreceptor (syndecan-4), and alpha4beta1 does not. Second, adhesion via alpha5beta1 caused an eightfold increase in protein kinase Calpha (PKCalpha) activation, but only basal PKCalpha activity was observed after adhesion via alpha4beta1. Pharmacological inhibition of PKCalpha and transient expression of dominant-negative PKCalpha, but not dominant-negative PKCdelta or PKCzeta constructs, suppressed focal adhesion formation and cell migration mediated by alpha5beta1, but had no effect on alpha4beta1. These findings demonstrate that different integrins can signal to induce focal adhesion formation and migration by different mechanisms, and they identify PKCalpha signaling as central to the functional differences between alpha4beta1 and alpha5beta1.
authors.affiliation: School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Mostafavi-Pour
authors.forename: Janet A
authors.initials: JA
authors.lastname: Askari
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Parkinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
authors.forename: Tony T C
authors.initials: TT
authors.lastname: Ng
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
mesh_terms: D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053671:Syndecan-4; D014407:Tumor Cells, Cultured; D000099221:Protein Kinase C zeta
chemical_list: D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D016023:Integrins; D008562:Membrane Glycoproteins; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011509:Proteoglycans; D053671:Syndecan-4; D000099221:Protein Kinase C zeta; C508304:SDC4 protein, human; C496628:PRKCA protein, human; C497258:PRKCD protein, human