Rap1 als zentrale Schaltstelle GLP-1 regulierter, mitogener Signalwege in pankreatischen beta-Zellen
Loading...
Files
Date
relationships.isAuthorOf
Publisher
Philipps-Universität Marburg
item.page.supervisor-of-thesis
Abstract
One of the key factors in the pathogenesis of type II diabetes mellitus is the dysfunction of the pancreatic beta cell. This dysfunction is characterized by a disturbed response to glucose and the loss of functional beta cell mass. The incretin hormone glucagon-like peptide-1 [GLP-1] not only lowers blood glucose levels by a direct effect on insulin sensitive tissues, but also functions as a growth factor for beta cells. GLP-1 leads to a dose- and glucose-dependent activation of the cAMP/PKA, PI3K/PKB and ERK1/2 MAPK. These three central mitogenic signaltransduction pathways are activated upon binding of GLP-1 to its G-protein coupled receptor. In contrast to other tissues in endocrine cells the signal transduction is not initiated by the prototype of small GTPases Ras but instead by Rap1.
The aim of this thesis was to examine the regulation and bindings partners of the GTPase Rap1 in beta cells stimulated with glucose and GLP-1. In addition identifying proteins which mediate the crosstalk between certain signal transduction cascades associated with Rap1 was a second field of exploration. The rat beta cell line INS 1E was employed as a model and the differential regulation of binding partners of Rap1 were identified by co-immunoprecepitation after stimulation with glucose and GLP-1.
The constitutive active RapGEF C3G was found to activate Rap1 depending on the phosphorylation of the adaptorprotein Crk II. As Crk II phosphorylation decreases upon stimulation with glucose and GLP-1 the ensuring conformational change leads to the activation of Rap1 by C3G. If the interaction of C3G and Crk II is blocked by introducing a dominant negative C3G CBR the activation of the downstream transcription factor Elk-1 is significantly reduced.
The interaction of Rap1 with IRS2 was shown to link the ERK1/2 MAPK path\-way with the PI3K/PKB pathway. This led to an activation of the PI3K/PKB pathway after stimulation of the cells with glucose and GLP-1.
The receptor independent tyrosine kinase Pyk2 could be indentified as a new element in the GLP-1 initiated signaltransduction cascade. Pyk2 interacts not only with Rap1, but also with IRS2 and thereby maybe influencing the two central mitogenic signal transduction pathways ERK1/2 MAPK and PI3K/PKB. The function of another newly identified binding partner of Rap1 - the adaptor protein Shc - is yet unclear. Based on these findings further studies into the role of Pyk2 and Shc in the signal transduction of GLP-1 are warranted.
The resuls of this thesis reveal new insights into the regulation and interactions of the small GTPase Rap1 in beta cells after GLP-1 stimulation. Understanding this process into full detail will lead to new strategies for the in vitro / in vivo expansion of beta cells for new therapeutic options in the treatment of diabetes mellitus.
Review
Metadata
Contributors
Supervisor:
Dates
Created: 2007Issued: 2007-11-05Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Type2 diabetes mellitusBeta-ZellenGLP-1Glucagon-like peptide-1Beta cellDiabetes mellitus Typ2Mitogenic signaltransductionRap1BetazellproliferationRap1
DFG-subjects
Diabetes mellitus Typ2BetazellproliferationGLP-1Rap1Beta-Zellen
DDC-Numbers
610
show more
Schrader, Donata: Rap1 als zentrale Schaltstelle GLP-1 regulierter, mitogener Signalwege in pankreatischen beta-Zellen. : Philipps-Universität Marburg 2007-11-05. DOI: https://doi.org/10.17192/z2007.0738.
License
This item has been published with the following license: In Copyright