Type I Collagen Signaling Regulates Opposing Fibrotic Pathways through α2β1 Integrin

Abstract The α2β1 integrin is a major collagen receptor on platelets. Although it has been proposed that α2β1, like αIIbβ3, undergoes agonist-induced activation, neither the potential contributions of α2β1 receptor/ligand internalization to the increase in ligand binding nor the roles of the α2 and β1 cytoplasmic domains in activation of this integrin have been previously explored. Activation of α2β1 was assessed with fluorescein isothiocyanate–labeled soluble type I collagen binding to platelets by flow cytometry. Although collagen internalization in response to agonist activation of platelets was significant, agonist-induced collagen binding still occurred under conditions that block internalization, with minimal changes in cell surface α2β1 expression. Introduction of cell-permeable peptides containing the α2 cytoplasmic tail, and especially the membrane proximal KLGFFKR domain, induced α2β1 activation in resting platelets, whereas a cell-permeable peptide containing the β1 cytoplasmic tail was without effect. Thus, collagen binding to stimulated platelets is increased due to α2β1 activation, in addition to internalization, and the GFFKR motif appears to play an important role in the activation process.

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Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the α2β1 integrin and PDGFβ receptor

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.10.031 ◽

2004 ◽

Vol 325 (1) ◽

pp. 328-337 ◽

Cited By ~ 35

Author(s):

Scott T. Hollenbeck ◽

Hiroyuki Itoh ◽

Otway Louie ◽

Peter L. Faries ◽

Bo Liu ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Type I Collagen ◽

Smooth Muscle Cell Proliferation ◽

Type I ◽

Α2β1 Integrin

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Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

Blood ◽

10.1182/blood-2007-08-107664 ◽

2008 ◽

Vol 111 (7) ◽

pp. 3562-3570 ◽

Cited By ~ 34

Author(s):

Karissa D. McCall-Culbreath ◽

Zhengzhi Li ◽

Mary M. Zutter

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Cell Activation ◽

Type I Collagen ◽

Innate Immune ◽

Mast Cell Activation ◽

Type I ◽

Matrix Metalloproteinase 1 ◽

Α2β1 Integrin

AbstractData from several investigators suggest that the α2β1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1, endorepellin, and several viruses, is required for innate immunity and regulation of autoimmune/allergic disorders. We demonstrated that the innate immune response to Listeria monocytogenes required α2β1 integrin expression by peritoneal mast cells (PMCs). Ligation of the α2β1 integrin by C1q contained in immune complexes comprised of Listeria and antibody was required for PMC activation in vitro and in vivo. However, ligation of the α2β1 integrin alone was insufficient to activate cytokine secretion, suggesting that one or more additional signals emanating from a coreceptor were required for PMC activation. Here, we demonstrate that C1q, but neither other complement proteins nor FcRγ, is required for early innate immune response to Listeria. The binding of Listeria's Internalin B (InlB) to hepatocyte growth factor receptor (HGF-R)/c-met provides the costimulatory function required for PMC activation. Either HGF or Listeria InlB bound to c-met and either C1q or type I collagen bound to α2β1 integrin stimulates PMC activation. These findings suggest that crosstalk between c-met and the α2β1 integrin may contribute to mast-cell activation in autoimmune and inflammatory disorders.

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Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function

Molecules ◽

10.3390/molecules24193489 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3489 ◽

Cited By ~ 1

Author(s):

Luciana S. Oliveira ◽

Maria Inácia Estevão-Costa ◽

Valéria G. Alvarenga ◽

Dan E. Vivas-Ruiz ◽

Armando Yarleque ◽

...

Keyword(s):

Metal Ion ◽

Type I Collagen ◽

Divalent Cations ◽

Type I ◽

Glycoprotein Vi ◽

Rich Domain ◽

Multidomain Structure ◽

A1 Domain ◽

Bothrops Atrox ◽

Α2β1 Integrin

Atroxlysin-III (Atr-III) was purified from the venom of Bothrops atrox. This 56-kDa protein bears N-linked glycoconjugates and is a P-III hemorrhagic metalloproteinase. Its cDNA-deduced amino acid sequence reveals a multidomain structure including a proprotein, a metalloproteinase, a disintegrin-like and a cysteine-rich domain. Its identity with bothropasin and jararhagin from Bothrops jararaca is 97% and 95%, respectively. Its enzymatic activity is metal ion-dependent. The divalent cations, Mg2+ and Ca2+, enhance its activity, whereas excess Zn2+ inhibits it. Chemical modification of the Zn2+-complexing histidine residues within the active site by using diethylpyrocarbonate (DEPC) inactivates it. Atr-III degrades plasma fibronectin, type I-collagen, and mainly the α-chains of fibrinogen and fibrin. The von Willebrand factor (vWF) A1-domain, which harbors the binding site for GPIb, is not hydrolyzed. Platelets interact with collagen via receptors for collagen, glycoprotein VI (GPVI), and α2β1 integrin. Neither the α2β1 integrin nor its collagen-binding A-domain is fragmented by Atr-III. In contrast, Atr-III cleaves glycoprotein VI (GPVI) into a soluble ~55-kDa fragment (sGPVI). Thereby, it inhibits aggregation of platelets which had been stimulated by convulxin, a GPVI agonist. Selectively, Atr-III targets GPVI antagonistically and thus contributes to the antithrombotic effect of envenomation by Bothrops atrox.

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The Thrombospondin Receptor CD47 (IAP) Modulates and Associates with α2β1 Integrin in Vascular Smooth Muscle Cells

Molecular Biology of the Cell ◽

10.1091/mbc.9.4.865 ◽

1998 ◽

Vol 9 (4) ◽

pp. 865-874 ◽

Cited By ~ 118

Author(s):

Xue-Qing Wang ◽

William A. Frazier

Keyword(s):

Smooth Muscle ◽

Monoclonal Antibodies ◽

Smooth Muscle Cells ◽

Type I Collagen ◽

Muscle Cells ◽

Type I ◽

Β1 Integrin ◽

Thrombospondin 1 ◽

Carboxyl Terminal ◽

Α2β1 Integrin

The carboxyl-terminal domain of thrombospondin-1 enhances the migration and proliferation of smooth muscle cells. Integrin-associated protein (IAP or CD47) is a receptor for the thrombospondin-1 carboxyl-terminal cell-binding domain and binds the agonist peptide 4N1K (kRFYVVMWKk) from this domain. 4N1K peptide stimulates chemotaxis of both human and rat aortic smooth muscle cells on gelatin-coated filters. The migration on gelatin is specifically blocked by monoclonal antibodies against IAP and a β1 integrin, rather than αvβ3 as found previously for 4N1K-stimulated chemotaxis of endothelial cells on gelatin. Both human and rat smooth muscle cells displayed a weak migratory response to soluble type I collagen; however, the presence of 4N1K peptide or intact thrombospondin-1 provoked a synergistic chemotactic response that was partially blocked by antibodies to α2 and β1 integrin subunits and to IAP. A combination of antiα2 and IAP monoclonal antibodies completely blocked chemotaxis. RGD peptide and antiαvβ3 mAb were without effect. 4N1K and thrombospondin-1 did not augment the chemotactic response of smooth muscle cells to fibronectin, vitronectin, or collagenase-digested type I collagen. Complex formation between α2β1 and IAP was detected by the coimmunoprecipitation of both α2 and β1 integrin subunits with IAP. These data suggest that IAP can associate with α2β1 integrin and modulate its function.

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