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A novel integrin ₅ß₁ binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells

Center for Cell and Vascular Biology, Children’s Research Institute, Columbus, Ohio 43205, USA

Correspondence to:
Correspondence to:
Dr D R Brigstock
Children’s Research Institute, Room WA2022, 700 Children’s Drive, Columbus, OH 43205, USA; brigstod{at}ccri.net

Background: Connective tissue growth factor (CCN2) is upregulated in pancreatic fibrosis and desmoplastic pancreatic tumours. CCN2 interacts with integrin ₅ß₁ on pancreatic stellate cells (PSC) in which it stimulates fibrogenesis, adhesion, migration, and proliferation.

Aim: To determine the structural domain(s) in CCN2 that interact with integrin ₅ß₁ to regulation PSC functions.

Methods: Primary activated rat PSC were tested for their adherence to isoforms of CCN2 comprising modules 1–4 (CCN2_1–4), modules 3–4 (CCN2_3–4), module 3 alone (CCN2₃), or module 4 alone (CCN2₄). Adhesion studies were performed in the presence of EDTA, divalent cations, anti-integrin ₅ß₁ antibodies, CCN2 synthetic peptides, or heparin, or after pretreatment of the cells with heparinase, chondroitinase, or sodium chlorate. CCN2 integrin ₅ß₁ binding was analysed in cell free systems. The ability of CCN2_1–4, CCN2_3–4, or CCN2₄ to stimulate PSC migration was evaluated in the presence of anti-integrin ₅ß₁ or heparin.

Results: PSC adhesion was stimulated by CCN2_1–4, CCN2_3–4, or CCN2₄ and supported by Mg²⁺ but not Ca²⁺. CCN2₄ supported PSC adhesion or migration were blocked by anti-integrin ₅ß₁ antibodies or by treatment of cells with heparinase or sodium chlorate. A direct interaction between CCN2₄ and integrin ₅ß₁ was demonstrated in cell free assays. The sequence GVCTDGR in module 4 mediated the binding between CCN2₄ and integrin ₅ß₁ as well as CCN2₄ mediated PSC adhesion and migration.

Conclusions: A GVCTDGR sequence in module 4 of CCN2 is a novel integrin ₅ß₁ binding site that is essential for CCN2 stimulated functions in PSC and which represents a new therapeutic target in PSC mediated fibrogenesis.

Abbreviations: BSA, bovine serum albumin; CCN2, connective tissue growth factor; ECM, extracellular matrix; FN, fibronectin; HSC, hepatic stellate cell; HSPG, heparan sulphate proteoglycan; MMPs, matrix metalloproteases; PSC, pancreatic stellate cell; TGF-ß, transforming growth factor ß

Keywords: pancreatitis; pancreatic fibrosis; fibrogenesis; connective tissue growth factor

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