Apoptotic calcium release from inositol 1,4,5-trisphosphate receptors (IP3Rs) regulates cell death in response to multiple stimuli, including engagement of the Fas receptor. We have found that the Fas receptor (FasR) directly engages and activates components of the T cell receptor complex (TCR) to elicit apoptotic calcium release from IP3R channels. However, the underlying molecular mechanisms remain to be established. Our preliminary data suggests that Fas and TCR components are recruited into detergent-resistant membrane microdomains enriched in cholesterol and glycosphingolipids (lipid rafts) following Fas stimulation. Furthermore, our data indicates that this is associated wih the rapid stimulus-dependent palmitoylation of the Src family kinase Lck. The central hypothesis of this proposal is that apoptotic calcium release is mediated by rapid palmitoylation of components of the Fas receptor complex, recruitment into lipid rafts, and subsequent activation of TCR components. We will investigate this hypothesis in two Specific Aims.
In Specific Aim 1, we will determine if recruitment of the FasR/TCR supramolecular signaling complex into lipid rafts mediates Fas-associated apoptotic calcium release.
In Specific Aim 2 : Determine if rapid stimulus-dependent palmitoylation/depalmitoylation of Lck by DHHC21 mediates Fas-associated apoptotic calcium release. We will use a variety of molecular biological, biochemical, and novel live cell imaging techniques to determine the mechanisms by which Fas receptor engages the TCR complex to mediate T lymphocyte calcium release and cell death. These studies may uncover novel therapeutic targets for diseases associated with altered T cell homeostasis.

Public Health Relevance

Many diseases are associated with defective T cell homeostasis. T cells numbers are regulated by a protein known as the Fas receptor. We will investigate in this project novel calcium-dependent pathways by which T cell death is regulated by the Fas receptor. As mutation of proteins in the Fas signaling pathway lead to autoimmunity and cancer, these studies may illuminate new therapeutic targets for disorders associated with altered T cell homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM081685-07S1
Application #
8826887
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Nie, Zhongzhen
Project Start
2007-08-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
7
Fiscal Year
2014
Total Cost
$64,767
Indirect Cost
$14,821
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Garcia, M Iveth; Boehning, Darren (2016) Cardiac inositol 1,4,5-trisphosphate receptors. Biochim Biophys Acta :
Akimzhanov, Askar M; Boehning, Darren (2015) Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling. Proc Natl Acad Sci U S A 112:11876-80
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Borahay, Mostafa A; Vincent, Kathleen; Motamedi, Massoud et al. (2015) Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study. Am J Obstet Gynecol 213:196.e1-8
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Wang, Xu; Xiong, Liang Wen; El Ayadi, Amina et al. (2013) The calmodulin regulator protein, PEP-19, sensitizes ATP-induced Ca2+ release. J Biol Chem 288:2040-8
Akimzhanov, Askar M; Barral, José M; Boehning, Darren (2013) Caspase 3 cleavage of the inositol 1,4,5-trisphosphate receptor does not contribute to apoptotic calcium release. Cell Calcium 53:152-8
Clark, Serena L; Rodriguez, Ana M; Snyder, Russell R et al. (2012) Structure-Function Of The Tumor Suppressor BRCA1. Comput Struct Biotechnol J 1:
Jeschke, Marc G; Boehning, Darren (2012) Endoplasmic reticulum stress and insulin resistance post-trauma: similarities to type 2 diabetes. J Cell Mol Med 16:437-44

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