Modulation of endocrine pancreas development but not beta-cell carcinogenesis by Sprouty4.
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.
Jäggi
Fabienne
F
Institute of Biochemistry and Genetics, Department of Clinical Biological Sciences, Center of Biomedicine, University of Basel, Basel, Switzerland.
Cabrita
Miguel A
MA
Perl
Anne-Karina T
AK
Christofori
Gerhard
G
D000818:Animals; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005951:Glucose Tolerance Test; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
C119724:AGFG1 protein, human; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C499037:Spry4 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases