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NFAT Binding and Regulation of T Cell Activation by the Cytoplasmic Scaffolding Homer Proteins
Guo N. Huang,1,2*
David L. Huso,3
Samuel Bouyain,4
Jianchen Tu,2
Kelly A. McCorkell,5
Michael J. May,5
Yuwen Zhu,6
Michael Lutz,7
Samuel Collins,7
Marlin Dehoff,2
Shin Kang,2
Katharine Whartenby,7
Jonathan Powell,7
Daniel Leahy,4
Paul F. Worley2,8
Abstract:
T cell receptor (TCR) and costimulatory receptor (CD28) signalscooperate in activating T cells, although understanding of howthese pathways are themselves regulated is incomplete. We foundthat Homer2 and Homer3, members of the Homer family of cytoplasmicscaffolding proteins, are negative regulators of T cell activation.This is achieved through binding of nuclear factor of activatedT cells (NFAT) and by competing with calcineurin. Homer-NFATbinding was also antagonized by active serine-threonine kinaseAKT, thereby enhancing TCR signaling via calcineurin-dependentdephosphorylation of NFAT. This corresponded with changes incytokine expression and an increase in effector-memory T cellpopulations in Homer-deficient mice, which also developed autoimmune-likepathology. These results demonstrate a further means by whichcostimulatory signals are regulated to control self-reactivity.
1 Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 2 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 4 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 5 Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. 6 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 7 Department of Oncology-Immunology/Hematopoiesis, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 8 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
* Present address: Department of Molecular Biology, Universityof Texas Southwestern Medical Center, Dallas, TX 75235, USA.
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: pworley{at}jhmi.edu
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These authors contributed equally to this work. 
To whom correspondence should be addressed. E-mail: 
