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Signaling Pathways Implicated in the Stimulation of β-Cell Proliferation by Extracellular Matrix

Department of Genetic Medicine and Development (G.P., E.H., P.R., P.A.H.), University of Geneva University Medical Center, and Cell Isolation and Transplantation Center (G.P., T.B.), Division of Surgical Research, Department of Surgery, University Hospital, CH-1211 Geneva, Switzerland; and Division of Endocrinology and Diabetes (M.Y.D.), University Hospital, CH-8091 Zurich, Switzerland

Address all correspondence and requests for reprints to: Geraldine Parnaud, Cell Isolation and Transplantation Center, Division of Surgical Research, Department of Surgery, University Hospital, Geneva, Switzerland, 1 rue Michel-Servet, CH-1211 Geneva-4, Switzerland. E-mail: geraldine.parnaud{at}unige.ch.

Laminin-5-rich extracellular matrix derived from 804G cells (804G-ECM) induces spreading, improves glucose-stimulated insulin secretion, and increases survival and proliferation of rat pancreatic β-cells. The aim of the study was to determine growth signaling pathways activated by ECM with a particular focus on Ca²⁺-dependent transcription factors. 804G-ECM increased rat β-cell proliferation, and this stimulation was glucose and Ca²⁺ dependent. NF-B nuclear translocation as well as IB gene expression were also Ca²⁺ dependent. Inhibition of NF-B almost completely blocked 804G-ECM-stimulated β-cell proliferation as did the soluble IL-1 receptor antagonist IL-1Ra. 804G-ECM-induced proliferation was also blocked by cyclosporin A and the VIVIT peptide, suggesting involvement of nuclear factor of activated T cells (NFAT)/calcineurin. Use of selective inhibitors further implicated other pathways in this process. Inhibition of phosphatidylinositol 3-kinase and protein kinase A both prevented β-cell replication stimulated by 804G-ECM. Conversely, inhibition of MAPK, c-Jun N-terminal kinase, p38, and glycogen synthase kinase-3β increased β-cell proliferation on 804G-ECM. Our results suggest that Ca²⁺ entry, which is necessary for increased β-cell proliferation on 804G-ECM, is also involved in 804G-ECM-induced NF-B activity. It is proposed that increased cytosolic Ca²⁺ leads to activation of the transcription factors NFAT and NF-B that in turn increase β-cell proliferation. Activation of phosphatidylinositol 3-kinase by 804G-ECM also increases proliferation possibly by synergistic coactivation of NFAT via inhibition of glycogen synthase kinase-3β, whereas IL-1β may amplify the process by feed-forward activation of NF-B. Conversely, inhibition of the MAPK pathway increased β-cell proliferation, indicating a counterregulatory restraining role for this signaling pathway.