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Fibroblast growth factor-induced signal transduction
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibroblast growth factors (FGFs) evoke cellular responses by binding to FGF receptors (FGFRs). FGFRs are cell surface expressed membrane-spanning receptors with intrinsic stimulatable tyrosine kinase activity. This thesis describes the cell proliferation or differentiation. Two new FGFR-1 substrates were identified, and intracellular signal transduction elicited by binding of FGF-2 to FGFR-1, leading to signal transduction molecules critical for FGF-2-stimulated endothelial cell differentiation were characterized.

The GTP-binding protein Ras is ubiquitously activated by growth factor receptors via recruitment of the Grb2/Sos complex. The adaptor protein Grb2 did not bind directly to FGFR-1. Instead, activation of FGFR-1 led to binding of Grb2 to either the Shc adaptor or to a novel adaptor protein, p89, both of which were tyrosine phosphorylated upon FGF-2 stimulation. Tyr766 in FGFR-1 was needed for a full mitogenic response, possibly involving binding of Shc. While Shc was found in the cytosol, p89 was targeted to the membrane. FGF-2, but not EGF or PDGF-BB,stimulation resulted in Grb2 binding to p89. Thus, FGFR-1 was shown to activate Ras via two distinct adaptor proteins, Shc and a novel FGFR-1 substrate, p89.

In the search for proteins potentially involved in FGFR-mediated cell-cycle regulation, we identified association between a Cdk-binding protein, p13suc, and a tyrosine phosphorylated component of about 70 kDa. The 70 kDa protein was purified and shown to correspond to the RNA-binding protein TLS (translocated in liposarcoma).TLS was bound to p13suc independent of growth factor stimulation but was tyrosine phosphorylated only after stimulation of cells with FGF-2, EGF, and PDGF-BB.

FGF stimulates angiogenesis in vitro and in vivo. The endothelial cell line IBEC presents an in vitro model for angiogenesis, in which the FGF-2-stimulated cells either proliferate or differentiate into tube-like structures, dependent on culture condition. We compared FGF-2-induced signal transduction in these proliferating and differentiating endothelial cells. The adaptor protein Shc linked FGFR-1 to Ras activation in both cellular responses, while the p89 adaptor coupled the receptor to Ras activation only in proliferating cells. Ras was shown by pharmacological inhibition or by expression of a dominant-negative mutant Ras, to be crucial for FGF-2-induced endothelial cell proliferation and differentiation, while expression of a constitutively active Ras mutant showed that Ras by itself, is not sufficient for endothelial cell differentiation. An inhibitor of the MEK and MAPK enzymes abrogated FGF-2-stimulated endothelial cell proliferation, but was without effect on differentiation of those cells. Inhibition of the serine kinase Raf-1 function by introduction of Raf-1 antisense oligonucleotides, or pharmacological inhibition of the tyrosine kinase Src, showed these two kinases to be essential for FGF-2-induced endothelial cell differentiation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 53 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 819
Keyword [en]
Biochemistry
Keyword [sv]
Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Cellbiology
Identifiers
URN: urn:nbn:se:uu:diva-941ISBN: 91-554-4385-0 (print)OAI: oai:DiVA.org:uu-941DiVA: diva2:172961
Public defence
1999-03-05, sal B41, Uppsala Biomedicinska Centrum, Uppsala, 09:15
Available from: 1999-02-12 Created: 1999-02-12Bibliographically approved

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