Jäggi Fabienne, Cabrita Miguel A, Perl Anne-Karina T, Christofori Gerhard
Institute of Biochemistry and Genetics, Department of Clinical Biological Sciences, Center of Biomedicine, University of Basel, Basel, Switzerland.
Mol Cancer Res. 2008 Mar;6(3):468-82. doi: 10.1158/1541-7786.MCR-07-0255.
Sprouty (Spry) proteins modulate signal transduction pathways elicited by receptor tyrosine kinases (RTK). Depending on cell type and the particular RTK, Spry proteins exert dual functions: They can either repress RTK-mediated signaling pathways, mainly by interfering with the Ras/Raf/mitogen-activated protein kinase pathway or sustaining RTK signal transduction, for example by sequestering the E3 ubiquitin-ligase c-Cbl and thus preventing ubiquitylation, internalization, and degradation of RTKs. Here, by the inducible expression of murine Spry4 in pancreatic beta cells, we have assessed the functional role of Spry proteins in the development of pancreatic islets of Langerhans in normal mice and in the Rip1Tag2 transgenic mouse model of beta-cell carcinogenesis. beta cell-specific expression of mSpry4 provokes a significant reduction in islet size, an increased number of alpha cells per islet area, and impaired islet cell type segregation. Functional analysis of islet cell differentiation in cultured PANC-1 cells shows that mSpry4 represses adhesion and migration of differentiating pancreatic endocrine cells, most likely by affecting the subcellular localization of the protein tyrosine phosphatase PTP1B. In contrast, transgenic expression of mSpry4 during beta-cell carcinogenesis does not significantly affect tumor outgrowth and progression to tumor malignancy. Rather, tumor cells seem to escape mSpry4 transgene expression.
Sprouty（Spry）蛋白可调节受体酪氨酸激酶（RTK）引发的信号转导通路。根据细胞类型和特定的RTK，Spry蛋白发挥双重功能：它们既可以抑制RTK介导的信号通路，主要是通过干扰Ras/Raf/丝裂原活化蛋白激酶通路，也可以维持RTK信号转导，例如通过隔离E3泛素连接酶c-Cbl，从而防止RTK的泛素化、内化和降解。在此，通过在胰腺β细胞中诱导表达小鼠Spry4，我们评估了Spry蛋白在正常小鼠胰岛发育以及β细胞癌变的Rip1Tag2转基因小鼠模型中的功能作用。mSpry4在β细胞中的特异性表达导致胰岛大小显著减小，每个胰岛区域的α细胞数量增加，以及胰岛细胞类型分离受损。对培养的PANC-1细胞中胰岛细胞分化的功能分析表明，mSpry4抑制分化中的胰腺内分泌细胞的黏附和迁移，最有可能是通过影响蛋白酪氨酸磷酸酶PTP1B的亚细胞定位。相反，在β细胞癌变过程中mSpry4的转基因表达不会显著影响肿瘤生长和向肿瘤恶性程度的进展。相反，肿瘤细胞似乎逃避了mSpry4转基因的表达。
