Integrin-associated protein stimulates alpha2beta1-dependent chemotaxis via Gi-mediated inhibition of adenylate cyclase and extracellular-regulated kinases.
Integrin-associated protein (IAP/CD47) augments the function of alpha2beta1 integrin in smooth muscle cells (SMC), resulting in enhanced chemotaxis toward soluble collagen (Wang, X-Q., and W.A. Frazier. 1998. Mol. Biol. Cell. 9:865). IAP-deficient SMC derived from IAP(-/-) animals did not migrate in response to 4N1K (KRFYVVMWKK), a peptide agonist of IAP derived from the COOH-terminal domain of thrombospondin-1 (TSP1). When normal SMC were preincubated with 4N1K or an anti-alpha2beta1 function-stimulating antibody, cell migration to soluble collagen was significantly enhanced. 4N1K-induced chemotaxis was blocked by treatment of SMC with pertussis toxin indicating that IAP acts through Gi. In agreement with this, 4N1K evoked a rapid decrease in cAMP levels which was intensified in the presence of collagen, and forskolin and 8-Br-cAMP both inhibited SMC migration stimulated via IAP. 4N1K strongly inhibited extracellular regulated kinase (ERK) activation in SMC attaching to collagen and reduced basal ERK activity in suspended SMC. Pertussis toxin treatment of SMC significantly activated ERK, suggesting that an inhibitory input was alleviated. Inhibition of ERK activity by (a) the MAP kinase kinase (MEK) inhibitor, PD98059, (b) antisense oligonucleotide depletion of ERK, and (c) expression of mitogen-activated protein (MAP) kinase phosphatase-1 in SMC all led to increased migration to collagen, 4N1K, or 4N1K plus collagen. Thus, IAP stimulates alpha2beta1 integrin-mediated SMC migration via Gi-mediated inhibition of ERK activity and suppression of cyclic AMP levels. Both of these signaling pathways could directly modulate the state of the integrin as well as impact downstream components of the cell motility apparatus.
Wang
X Q
XQ
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lindberg
F P
FP
Frazier
W A
WA
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology / Q000502:physiology; D038981:Receptors, Collagen; D015398:Signal Transduction / Q000187:drug effects
C120273:4N1K peptide; D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D016023:Integrins; D009842:Oligopeptides; D038981:Receptors, Collagen; D000242:Cyclic AMP; D019204:GTP-Binding Proteins