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Figure 3. Simplified model of integration between the Ca2+ and SOS-Ras-ERK1/2 and Smad signaling pathways as a putative mechanism for gingival overgrowth. As a response to, e.g., growth factor stimulation, intracellular Ca2+-ion concentration can locally increase as a result of the release of Ca2+ from intracellular stores (endoplasmic reticulum or mitochondria), or by changes in the function of cell-membrane ion pumps (e.g., NCX1) that regulate Ca2+ influx and efflux. Local Ca2+ transients can induce SOS-1/Grb2-mediated activation of Ras, leading to phosphorylation and activation of downstream signaling pathways, including ERK1/2 of the MAPK pathway. Ca2+ can also bind to calmodulin (CaM), and this complex down-regulates Ras-mediated ERK1/2 activation and the TGF-ß-regulated Smad pathway in fibroblasts. CaM/Ca2+ can also induce activation of Ras and calmodulin-dependent protein kinases (CaMKs), including CaMKIV. Neurofibromin (NF) accelerates inactivation of GTP-bound Ras. Activation of the TGF-ß-receptor by TGF-ß activates the Smad and Ras-ERK1/2 pathways. At the transcriptional level, CaMKIV through p300/CBP (CREB-binding protein), ERK1/2 through AP-1 (activating protein-1), and Smads collaborate to regulate pro-fibrotic gene expression and cell proliferation in fibroblasts.
