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 β-cells. The aim of the study was to determine growth signaling pathways activated by ECM with a particu...

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Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2009-08, Vol.23 (8), p.1264-1271
Main Authors: Parnaud, Géraldine, Hammar, Eva, Ribaux, Pascale, Donath, Marc Y, Berney, Thierry, Halban, Philippe A
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Cell Adhesion Molecules - chemistry
Cell Proliferation
Extracellular Matrix - metabolism
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Insulin-Secreting Cells - cytology
JNK Mitogen-Activated Protein Kinases - metabolism
Kalinin
Male
MAP Kinase Signaling System
NF-kappa B - metabolism
Original Research
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Rats
Rats, Wistar
Signal Transduction
Transcription Factors - metabolism
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Summary: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-κB nuclear translocation as well as IκBα gene expression were also Ca2+ dependent. Inhibition of NF-κB 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-κB activity. It is proposed that increased cytosolic Ca2+ leads to activation of the transcription factors NFAT and NF-κB 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-κB. Conversely, inhibition of the MAPK pathway increased β-cell proliferation, indicating a counterregulatory restraining role for this signaling pathway. Extracellular matrix increases proliferation of rat pancreatic beta cells in a glucose-dependent fashion by raising cytosolic Ca2+ and activating the transcription factors NFAT and NF-κB.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2009-0008