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- Annerén, Cecilia, et al.
(author)
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The FRK/RAK-SHB signaling cascade : a versatile signal-transduction pathway that regulates cell survival, differentiation and profileration
- 2003
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In: Current molecular medicine. - : Bentham. - 1566-5240 .- 1875-5666. ; 3:4, s. 313-324
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Journal article (peer-reviewed)abstract
- Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK / RAK (also named BSK / IYK or GTK). FRK / RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and β-cells, where they both induce PC12 cell differentiation and β-cell proliferation. Furthermore, β-cell apoptosis is augmented by these proteins under conditions that cause β-cell degeneration. The FRK / RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2.Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development.In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.
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- Welsh, Michael, et al.
(author)
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Role of tyrosine kinase signaling for b-cell replication and survival
- 2000
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In: Upsala Journal of Medical Sciences, Supplement. - 0300-9726 .- 0300-9734 .- 2000-1967. ; 105:2, s. 7-15
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Journal article (peer-reviewed)abstract
- 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.
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