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

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 beta-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 beta-cell proliferation, and this stimulation was glucose and Ca2+ dependent. NF-kappa B nuclear translocation as well as I kappa B alpha gene expression were also Ca2+ dependent. Inhibition of NF-kappa B almost completely blocked 804G-ECM-stimulated beta-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 beta-cell replication stimulated by 804G-ECM. Conversely, inhibition of MAPK, c-Jun N-terminal kinase, p38, and glycogen synthase kinase-3 beta increased beta-cell proliferation on 804G-ECM. Our results suggest that Ca2+ entry, which is necessary for increased beta-cell proliferation on 804G-ECM, is also involved in 804G-ECM-induced NF-kappa B activity. It is proposed that increased cytosolic Ca2+ leads to activation of the transcription factors NFAT and NF-kappa B that in turn increase beta-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-3 beta, whereas IL-1 beta may amplify the process by feed-forward activation of NF-kappa B. Conversely, inhibition of the MAPK pathway increased beta-cell proliferation, indicating a counterregulatory restraining role for this signaling pathway. (Molecular Endocrinology 23: 1264-1271, 2009)