Publication Date:
2008-01-26
Description:
T cell receptor (TCR) and costimulatory receptor (CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells (NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine-threonine kinase AKT, thereby enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice, which also developed autoimmune-like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self-reactivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Guo N -- Huso, David L -- Bouyain, Samuel -- Tu, Jianchen -- McCorkell, Kelly A -- May, Michael J -- Zhu, Yuwen -- Lutz, Michael -- Collins, Samuel -- Dehoff, Marlin -- Kang, Shin -- Whartenby, Katharine -- Powell, Jonathan -- Leahy, Daniel -- Worley, Paul F -- DA00266/DA/NIDA NIH HHS/ -- DA10309/DA/NIDA NIH HHS/ -- P30 CA006973/CA/NCI NIH HHS/ -- R01 CA098109/CA/NCI NIH HHS/ -- T32 CA009140/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2008 Jan 25;319(5862):476-81. doi: 10.1126/science.1151227.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18218901" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD28/immunology
;
Antigens, CD3/immunology
;
Calcineurin/metabolism
;
Calcium/metabolism
;
Carrier Proteins/chemistry/*metabolism
;
Cell Line
;
Cells, Cultured
;
Crystallography, X-Ray
;
Humans
;
Jurkat Cells
;
*Lymphocyte Activation
;
Mice
;
Mice, Knockout
;
NFATC Transcription Factors/chemistry/*metabolism
;
Phosphorylation
;
Protein Structure, Tertiary
;
Proto-Oncogene Proteins c-akt/metabolism
;
Recombinant Fusion Proteins/metabolism
;
Signal Transduction
;
T-Lymphocytes/*immunology/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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