ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs
ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs
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DOI：
10.1073/pnas.0710931105
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发表时间：
2008-01-15
影响因子：
11.1
通讯作者：
Solimena, Michele
中科院分区：
文献类型：
--
作者：
Mziaut, Hassan;Kersting, Stephan;Solimena, Michele
代谢需求的变化动态调节成年胰腺β细胞的总质量，以调节胰岛素分泌并保持葡萄糖稳态。葡萄糖本身通过诱导胰岛素分泌和激活β细胞胰岛素受体是β细胞增殖的主要调节剂。在这里，我们表明，胰岛细胞自身抗原512（ICA 512）/IA-2，内在的酪氨酸磷酸酶样蛋白的分泌颗粒，激活β细胞增殖的互补途径。在颗粒胞吐时，ICA 512胞质结构域被切割，所得胞质片段（ICA 512-CCF）移动到细胞核中，在细胞核中其增强磷酸化STAT 5和STAT 3的水平，从而诱导胰岛素基因转录和颗粒生物发生。我们现在发现，ICA 512的敲低降低了细胞周期蛋白D1水平和胰岛素瘤INS-1细胞的增殖，而在部分胰腺切除的ICA 512（-/-）小鼠中，β细胞再生减少。相反，ICAS 12-CCF的过表达增加了细胞周期蛋白D1和D2水平以及INS-1细胞增殖。ICA 512-CCF对细胞周期蛋白D1和D2的上调分别受到STAT 3和STAT 5敲低的影响，而它不需要胰岛素信号。这些结果确定ICA 512作为细胞周期蛋白D和通过STAT的β细胞增殖的调节剂，并且可能对糖尿病治疗有意义。
Changes in metabolic demands dynamically regulate the total mass of adult pancreatic beta-cells to adjust insulin secretion and preserve glucose homeostasis. Glucose itself is a major regulator of beta-cell proliferation by inducing insulin secretion and activating beta-cell insulin receptors. Here, we show that islet cell autoantigen 512 (ICA512)/IA-2, an intrinsic tyrosine phosphatase-like protein of the secretory granules, activates a complementary pathway for beta-cell proliferation. On granule exocytosis, the ICA512 cytoplasmic domain is cleaved and the resulting cytosolic fragment (ICA512-CCF) moves into the nucleus where it enhances the levels of phosphorylated STAT5 and STAT3, thereby inducing insulin gene transcription and granule biogenesis. We now show that knockdown of ICA512 decreases cyclin D1 levels and proliferation of insulinoma INS-1 cells, whereas beta-cell regeneration is reduced in partially pancreatectornized ICA512(-/-) mice. Conversely, overexpression of ICAS12-CCF increases both cyclin D1 and D2 levels and INS-1 cell proliferation. Up-regulation of cyclin D1 and D2 by ICA512-CCF is affected by knockdown of STAT3 and STAT5, respectively, whereas it does not require insulin signaling. These results identify ICA512 as a regulator of cyclins D and beta-cell proliferation through STATs and may have implication for diabetes therapy.