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B cell antigen receptor signalling : regulation and targets of the P13K/AKT pathway Christian, Sherri Lynn
Abstract
The B cell receptor (BCR) is a major regulator of B cell development, activation, and cell death. The misregulation of these processes results in autoimmunity and B cell lymphoma. Engagement of the BCR activates multiple signalling pathways that are essential for normal B cell responses. However, the roles of individual signalling pathways in mediating these responses is not completely understood. Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is important for the proper regulation of B cell survival and development. In this thesis I have investigated the regulation and targets of the PI3K pathway in B cells. A putative target of the PI3K pathway is β-catenin, a transcriptional activator with important roles in early development. I found that the BCR regulates β-catenin levels via the activation of the phospholipase-C/protein kinase C/glycogen synthase kinase-3 pathway and is partially dependent on PI3K. Signalling by the BCR also activates the Rap GTPases, putative antagonists of Ras-mediated signalling. Ras can activate both the Raf-1/ERK 1/21/2 pathway and the PI3K/Akt pathway, pathways that can promote cell survival. I investigated whether Rap activation limits the activation of either of these pathways. I found that Rap activation had no effect on the BCR-induced activation of the Raf-1/ERK1/21/2 pathway. However, endogenous Rap limited the BCRinduced activation of the POK/Akt pathway, opposed the Akt-mediated inhibition of the FKHR/p27[sup Kip1] pro-apoptotic module, and enhanced cell death. Therefore, Rap can oppose the pro-survival role of the PI3K pathway. BCR-induced activation of the PI3K effector Akt leads to changes in gene transcription through the Akt-mediated activation or inhibition of transcription factors which can promote cell survival. I used cDNA microarray technology to identify novel gene targets of Akt in B cells. I found that Akt activation resulted in changes in expression of genes involved in the regulation of cell cycle progression, cell adhesion and apoptosis. In summary, I have identified novel targets and novel mechanisms of regulating the PI3K/Akt pathway in B cells. This work will hopefully contribute to the overall understanding of how the PI3K pathway affects the regulation of B cell development, activation, and survival.
Item Metadata
Title |
B cell antigen receptor signalling : regulation and targets of the P13K/AKT pathway
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2004
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Description |
The B cell receptor (BCR) is a major regulator of B cell development, activation, and cell death. The misregulation of these processes results in autoimmunity and B cell lymphoma. Engagement of the BCR activates multiple signalling pathways that are essential for normal B cell responses. However, the roles of individual signalling pathways in mediating these responses is not completely understood. Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is important for the proper regulation of B cell survival and development. In this thesis I have investigated the regulation and targets of the PI3K pathway in B cells. A putative target of the PI3K pathway is β-catenin, a transcriptional activator with important roles in early development. I found that the BCR regulates β-catenin levels via the activation of the phospholipase-C/protein kinase C/glycogen synthase kinase-3 pathway and is partially dependent on PI3K. Signalling by the BCR also activates the Rap GTPases, putative antagonists of Ras-mediated signalling. Ras can activate both the Raf-1/ERK 1/21/2 pathway and the PI3K/Akt pathway, pathways that can promote cell survival. I investigated whether Rap activation limits the activation of either of these pathways. I found that Rap activation had no effect on the BCR-induced activation of the Raf-1/ERK1/21/2 pathway. However, endogenous Rap limited the BCRinduced activation of the POK/Akt pathway, opposed the Akt-mediated inhibition of the FKHR/p27[sup Kip1] pro-apoptotic module, and enhanced cell death. Therefore, Rap can oppose the pro-survival role of the PI3K pathway. BCR-induced activation of the PI3K effector Akt leads to changes in gene transcription through the Akt-mediated activation or inhibition of transcription factors which can promote cell survival. I used cDNA microarray technology to identify novel gene targets of Akt in B cells. I found that Akt activation resulted in changes in expression of genes involved in the regulation of cell cycle progression, cell adhesion and apoptosis. In summary, I have identified novel targets and novel mechanisms of regulating the PI3K/Akt pathway in B cells. This work will hopefully contribute to the overall understanding of how the PI3K pathway affects the regulation of B cell development, activation, and survival.
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Genre | |
Type | |
Language |
eng
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Date Available |
2009-12-16
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0092246
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2004-05
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.