Distinct ligand binding sites in integrin alpha3beta1 regulate matrix adhesion and cell-cell contact.
The integrin alpha3beta1 mediates cellular adhesion to the matrix ligand laminin-5. A second integrin ligand, the urokinase receptor (uPAR), associates with alpha3beta1 via a surface loop within the alpha3 beta-propeller (residues 242-246) but outside the laminin binding region, suggesting that uPAR-integrin interactions could signal differently from matrix engagement. To explore this, alpha3-/- epithelial cells were reconstituted with wild-type (wt) alpha3 or alpha3 with Ala mutations within the uPAR-interacting loop (H245A or R244A). Wt or mutant-bearing cells showed comparable expression and adhesion to laminin-5. Cells expressing wt alpha3 and uPAR dissociated in culture, with increased Src activity, up-regulation of SLUG, and down-regulation of E-cadherin and gamma-catenin. Src kinase inhibition or expression of Src 1-251 restored the epithelial phenotype. The H245A and R244A mutants were unaffected by coexpression of uPAR. We conclude that alpha3beta1 regulates both cell-cell contact and matrix adhesion, but through distinct protein interaction sites within its beta-propeller. These studies reveal an integrin- and Src-dependent pathway for SLUG expression and mesenchymal transition.
Zhang
Feng
F
Pulmonary and Critical Care Division, University of California San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0130, USA.
Tom
Clifford C
CC
Kugler
Matthias C
MC
Ching
Tsui-Ting
TT
Kreidberg
Jordan A
JA
Wei
Ying
Y
Chapman
Harold A
HA
D019943:Amino Acid Substitution; D001665:Binding Sites / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D004848:Epithelium / Q000378:metabolism; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D015820:Cadherins; D039201:Integrin alpha3beta1; D008024:Ligands; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019061:src-Family Kinases