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Roles of the Shb and Cbl Proteins in Signal Transduction and Blood Vessel Formation
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Formation of blood vessels occurs through two processes: vasculogenesis and angiogenesis, which are regulated by various growth factors such as vascular endothelial growth factor, fibroblast growth factor and platelet-derived growth factor. The present study was carried out in order to investigate the roles of the Shb and Cbl proteins in growth factor-mediated signal transduction and blood vessel formation. Shb was found to be involved in NGF-stimulated Rap1 signaling in PC12 cells by forming a complex with CrkII and a 130-135 kDa protein. The Rap1 signaling pathway contributed to NGF-dependent neurite outgrowth. In immortomouse brain endothelial (IBE) cells, Shb increased cell spreading, migration and cytoskeletal rearrangements. Such effects may partly be due to altered Rap1 activation in Shb overexpressing IBE cells. Shb was required for tubular morphogenesis in collagen gels in the presence of FGF-2. In embryoid bodies (EBs) derived from murine embryonic stem cells, Shb up-regulated both VEGFR2 and Tal1 expression at early stages of EB development and thus promoted blood vessel formation both in the absence and in the presence of growth factors. In IBE cells, Cbl positively regulated FGF-2 signaling and increased cell proliferation. Mutation of RING finger alone did not affect blood vessel formation in EBs. However, EBs overexpressing the oncogenic form Cbl 70Z, which had a deletion of the linker region and the first cysteine of the RING finger, exhibited intense CD31 positive sheet-like staining and blood vessel. The results suggested that Cbl had dual roles in endothelial cells: it promoted FGF-2-induced proliferation whereas down-regulated proliferation of endothelial progenitor cells.

The present work suggests that Shb and Cbl play a crucial role in cell differentiation and blood vessel formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 49
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1270
Keywords [en]
Cell biology, Shb, Cbl, FGF-2, NGF, PDGF, VEGF, VEGFR-2, differentiation, blood vessel formation, PC12 cells, endothelial cells, embryoid bodies, Rap1, CrkII
Keywords [sv]
Cellbiologi
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-3491ISBN: 91-554-5653-7 (print)OAI: oai:DiVA.org:uu-3491DiVA, id: diva2:163017
Public defence
2003-06-05, C2-301, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-05-13 Created: 2003-05-13 Last updated: 2018-01-13Bibliographically approved
List of papers
1. NGF-dependent neurite outgrowth in PC12 cells overexpressing the Src homology 2-domain protein Shb requires activation of the Rap1 pathway
Open this publication in new window or tab >>NGF-dependent neurite outgrowth in PC12 cells overexpressing the Src homology 2-domain protein Shb requires activation of the Rap1 pathway
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2000 (English)In: Exp. Cell Res., Vol. 259, no 2, p. 370-377Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90598 (URN)
Available from: 2003-05-13 Created: 2003-05-13 Last updated: 2012-12-17
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