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GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway: Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2000 (English)In: J Biol Chem, Vol. 275, 29153-29161 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 275, 29153-29161 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89444OAI: oai:DiVA.org:uu-89444DiVA: diva2:160877
Available from: 2001-09-25 Created: 2001-09-25 Last updated: 2012-12-17
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.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1062
Keyword
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
Identifiers
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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Annerén, CeciliaWelsh, M

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