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Identification of Novel Signaling Pathways in T Cells Mediated by Protein Kinase C, Carma1, MALT1 and Bcl10

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 (Unpublished)

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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Status: Unpublished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:
CreatorsEmailPitt UsernameORCID
Hamilton, Kristia Sksh21@pitt.eduKSH21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKane, Lawrence Plkane@pitt.eduLKANE
Committee MemberGaffen, Sarah Lsig65@pitt.eduSIG65
Committee MemberJiang, Yuyuj5@pitt.eduYUJ5
Committee MemberLu, Binfengbinfeng@pitt.eduBINFENG
Committee MemberRay, Prabirrayp@pitt.eduRAYP
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: 15 Nov 2016 14:21
URI: http://d-scholarship.pitt.edu/id/eprint/21925

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