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Dual role of the tyrosine kinase GTK and the adaptor protein SHB in β-cell growth: enhanced β-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2002 (English)In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 0022-0795, Vol. 172, no 1, 145-153 p.Article in journal (Refereed) Published
Abstract [en]

Transgenic CBA mice expressing either the tyrosine kinase GTK (gut tyrosine kinase) or the adaptor protein SHB (Src homology 2 protein of beta-cells) under the control of the rat insulin promoter exhibited an increased beta-cell mass, but also elevated cytokine-induced islet cell death compared with control mice. To further investigate the importance of GTK and SHB for beta-cell death and proliferation, these mice were subjected to a 60% partial pancreatectomy (Px) or a sham-operation and beta-cell replication was determined by autoradiographic detection of [(3)H]thymidine incorporation into islet cells positively stained for insulin. The Px-operated control mice exhibited a moderate and insignificant increase in beta-cell replication 4 days after Px compared with the sham-operated mice (0.27+/-0.08% vs 0.08+/-0.02%). In contrast, the Px-induced beta-cell proliferation was significantly increased in both the GTK- and SHB-transgenic mice compared with the corresponding sham-treated animals (0.64+/-0.12% vs 0.11+/-0.04% and 0.44+/-0.11% vs 0.09+/-0.04% respectively). This effect was dependent on intracellular signal transduction pathways activated or enhanced by GTK and SHB overexpression, since the proliferation of acinar cells, located in the vicinity of the islets, was equal in the transgenic and control mice. GTK- and SHB-transgenic mice, treated with a sub-diabetogenic dose of the beta-cell toxin streptozotocin (STZ) on day 0 and subjected to a glucose tolerance test on day 3, exhibited an impaired glucose tolerance in comparison with the STZ-treated control mice. Pretreatment with STZ blunted the regenerative response to Px in the transgenic mice. Furthermore, the SHB-transgenic islets were significantly more damaged with respect to beta-cell loss, compared with the islets of the control mice. Previous and present data suggest a dual role of GTK and SHB for beta-cell growth: whereas these proteins increase the beta-cell mass and induce beta-cell proliferation after 60% Px, SHB and GTK also enhance beta-cell death under certain stressful conditions.

Place, publisher, year, edition, pages
2002. Vol. 172, no 1, 145-153 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89442DOI: 10.1677/joe.0.1720145ISI: 000173471200013PubMedID: 11786382OAI: oai:DiVA.org:uu-89442DiVA: diva2:160875
Available from: 2001-09-25 Created: 2001-09-25 Last updated: 2011-06-28Bibliographically approved
In thesis
1. The Tyrosine Kinase GTK: Signal Transduction and Biological Function
Open this publication in new window or tab >>The Tyrosine Kinase GTK: Signal Transduction and Biological Function
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Protein tyrosine kinases play an important role in the regulation of various cellular processes such as

growth, differentiation and survival. GTK, a novel SRC-like cytoplasmic tyrosine kinase, was recently cloned from a mouse insulinoma cell line and the present work was conducted in order to find a biological function of GTK in insulin producing and neuronal cells. It was observed that kinase active GTK-mutants, expressed in RINm5F cells, transferred to the cell nucleus and increased the levels of the cell cycle regulatory protein p27KIP1, reduced cell growth and stimulated glucagon mRNA expression. Furthermore, wild type GTK induces neurite outgrowth in the rat adrenal pheochromocytoma PC12 cell line, through activation of the RAP1-pathway, suggesting a role of GTK for cell differentiation. Studies using transgenic mice, expressing GTK under the control of the rat insulin 1 promoter, demonstrated a dual role of GTK for β-cell growth: Whereas GTK increases the β-cell mass and causes enhanced β-cell proliferation in response to partial pancreatectomy it also induced β-cell death in response to proinflammatory cytokines and impaired the glucose tolerance in mice treated with the β-cell toxin streptozotocin suggesting a possible role of GTK for β-cell destruction in Type 1 diabetes. We have also observed that GTK-transgenic islets and GTK-expressing RINm5F cells exhibit a reduced insulininduced activation of the insulin receptor substrate (IRS-1 and IRS-2)-pathways, partly due to an increased basal activity of these. GTK was found to associate with and phosphorylate the SH2 domain adapter protein SHB, which could explain many of the GTK-dependent effects both in vitro and in vivo. In summary, the present work suggests that the novel tyrosine kinase GTK is involved in various signal transduction pathways, regulating different cellular responses, such as proliferation, differentiation and survival.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 56 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1062
Cell biology, Protein tyrosine kinases, GTK, SHB, proliferation, survival, differentiation, β cells, pancreatectomy, cytokines, diabetes, PC12 cells, NGF, streptozotocin, focal adhesion kinase, RAP1, Cellbiologi
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-1384 (URN)91-554-5082-2 (ISBN)
Public defence
2001-09-21, lecture hall B21, Biomedical Centre (BMC), Uppsala, 09:15
Available from: 2001-09-25 Created: 2001-09-25Bibliographically approved

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