Hamilton, Kristia S
(2014)
Identification of Novel Signaling Pathways in T Cells Mediated by Protein Kinase C, Carma1, MALT1 and Bcl10.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Stimulation of T cells through the T cell receptor (TCR) and co-stimulatory molecules induces a diverse set of signaling events leading to T cell activation. Some characteristics of T cell activation are cellular proliferation, increase in cell size and changes in metabolic pathways. Our work has primarily focused on understanding the roles that PKC and Carma1, MALT1 and Bcl10 (the CBM complex) play in T cell activation, specifically, elucidating their requirement in distinct T cell signaling pathways. Here, I have shown a requirement for PKC, Carma1 and MALT1 in activation of the mTORC1 pathway. Inhibition of PKC impaired TCR-dependent S6 phosphorylation and that this requires Carma1 and the MEK/ERK pathways. In the absence of Carma1 or MALT1, we noted impaired TCR/CD28-induced stimulation of ribosomal protein S6, p70S6K and 4E-BP1 phosphorylation. Pharmacological inhibition of this pathway with a MALT1 protease inhibitor (z-VRPR-fmk) impaired T cell proliferation and activation-induced glycolysis, as seen by a decrease in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Thus, these findings present a novel mechanism for mTORC1 activation in T cells, through Carma1 and MALT1, leading to cellular proliferation and increased glycolysis. Surprisingly, Bcl10 was not required for S6 or S6K phosphorylation in T cells. We also demonstrate that MALT1 regulates stimulation dependent S6 phosphorylation in the ABC-DLBCL subtype. Here, we have identified novel signaling pathways whereby the proteins PKC, Carma1 and MALT1 activate the mTORC1 pathway. Our findings will provide new avenues for current therapies in dysregulated T cells.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Hamilton, Kristia S | ksh21@pitt.edu | KSH21 | |
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| ETD Committee: |
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| Date: |
24 June 2014 |
| Date Type: |
Publication |
| Defense Date: |
4 June 2014 |
| Approval Date: |
24 June 2014 |
| Submission Date: |
19 June 2014 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
140 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
T cells, signaling, Protein Kinase C, Carma1, MALT1, Bcl10, mTOR |
| Date Deposited: |
24 Jun 2014 18:08 |
| Last Modified: |
24 Jun 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/21925 |
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