Role of tyrosine kinase signaling for beta-cell replication and survival.
Diabetes mellitus is commonly considered as a disease of a scant beta-cell mass that fails to respond adequately to the functional demand. Tyrosine kinases may play a role for beta-cell replication, differentiation (neoformation) and survival. Transfection of beta-cells with DNA constructs coding for tyrosine kinase receptors yields a ligand-dependent increase of DNA synthesis in beta-cells. A PCR-based technique was adopted to assess the repertoire of tyrosine kinases expressed in fetal islet-like structures, adult islets or RINm5F cells. Several tyrosine kinase receptors, such as the VEGFR-2 (vascular endothelial growth factor receptor 2) and c-Kit, were found to be present in pancreatic duct cells. Because ducts are thought to harbor beta-cell precursor cells, these receptors may play a role for the neoformation of beta-cells. The Src-like tyrosine kinase mouse Gtk (previously named Bsk/Iyk) is expressed in islet cells, and was found to inhibit cell proliferation. Furthermore, it conferred decreased viability in response to cytokine exposure. Shb is a Src homology 2 domain adaptor protein which participates in tyrosine kinase signaling. Transgenic mice overexpressing Shb in beta-cells exhibit an increase in the neonatal beta-cell mass, an improved glucose homeostasis, but also decreased survival in response to cytokines and streptozotocin. It is concluded that tyrosine kinase signaling may generate multiple responses in beta-cells, involving proliferation, survival and differentiation.
Welsh
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M
Department of Medical Cell Biology, Uppsala University, Sweden. Michael.Welsh@medcellbiol.uu.se
Annerén
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Lindholm
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Kriz
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Oberg-Welsh
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division; D002470:Cell Survival; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D011518:Proto-Oncogene Proteins; C490081:SHB protein, human; C085634:Shb protein, mouse; C100882:gtk kinase; D011505:Protein-Tyrosine Kinases