Fibroblast growth factor receptor-1 signaling in pancreatic islet β-cells is modulated by the extracellular matrix
Fibroblast growth factor receptor-1 signaling in pancreatic islet β-cells is modulated by the extracellular matrix
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DOI：
10.1210/me.2007-0241
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发表时间：
2008-01-01
影响因子：
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通讯作者：
Rocheleau, Jonathan V.
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文献类型：
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作者：
Kilkenny, Dawn M.;Rocheleau, Jonathan V.
胰岛β细胞质量的维持依赖于促进生存和增殖的细胞外刺激。在胰岛，这些刺激来自β细胞微环境，包括相关血管内皮细胞沉积的细胞外基质。成纤维细胞生长因子受体-1(FGFR1)最近被认为是一条对正常的β细胞功能至关重要的信号通路。我们想了解细胞外基质和FGFR1信号如何相互作用来促进β细胞的存活和增殖。为了检测β细胞特异性受体反应，我们创建了慢病毒载体，由大鼠胰岛素启动子驱动表达金星荧光蛋白标记的全长(R1βv)和激酶缺陷(KDR1βv)FGFR1。在βTC3细胞、散在的β细胞和完整胰岛的β细胞中观察到显著的依赖于FGF-1的ERK1/2的激活。这种反应被R1βv的表达增强，而被KDR1βv的表达降低。分散在IV型胶原上的β细胞可增强内源性FGFR1的表达，这与ERK1/2的持续激活有关。相反，将细胞接种在层粘连蛋白上可降低FGFR1的表达。加入中和抗体以抑制β细胞通过α(6)-整合素与层粘连蛋白的附着增加了高亲和力的成纤维细胞生长因子-1结合在质膜上，并导致持续的ERK1/2活性，类似于在IV型胶原上培养的细胞。这些数据表明，成纤维细胞生长因子刺激的β细胞反应受α(6)-整合素与层粘连蛋白结合的负面影响，提示与血管内皮细胞重塑相关的调控。
Maintenance of pancreatic beta-cell mass depends on extracellular stimuli that promote survival and proliferation. In the islet, these stimuli come from the beta-cell microenvironment and include extracellular matrix deposited by associated vascular endothelial cells. Fibroblast growth factor receptor-1 (FGFR1) has recently been implicated as a signaling pathway that is important for normal beta-cell function. We would like to understand how extracellular matrix and FGFR1 signaling interact to promote beta-cell survival and proliferation. To examine beta-cell-specific receptor responses, we created lentiviral vectors with rat insulin promoter-driven expression of Venus fluorescent protein-tagged full-length (R1 beta v) and kinase-deficient (KDR1 beta v) FGFR1. Significant FGF-1-dependent activation of ERK1/2 was observed in beta TC3 cells, dispersed beta-cells, and beta-cells in intact islets. This response was enhanced by R1 beta v expression and reduced by KDR1 beta v expression. Plating-dispersed beta-cells on collagen type IV resulted in enhanced expression of endogenous FGFR1 that was associated with sustained activation of ERK1/2. Conversely, plating cells on laminin reduced expression of FGFR1, and this reduction was associated with transient activation of ERK1/2. Addition of neutralizing antibodies to inhibit beta-cell attachment to laminin via alpha(6)-integrin increased high-affinity FGF-1-binding at the plasma membrane and resulted in sustained ERK1/2 activity similar to cells plated on collagen type IV. These data show that the FGF-stimulated beta-cell response is negatively affected by alpha(6)-integrin binding to laminin and suggest regulation associated with vascular endothelial cell remodeling.