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Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade
Authors
Bunnell, Stephen C.Diehn, Maximilian
Yaffe, Michael B.
Findell, Paul R.
Cantley, Lewis C.
Berg, Leslie J.
UMass Chan Affiliations
Department of PathologyDocument Type
Journal ArticlePublication Date
2000-01-15Keywords
*Adaptor Proteins, Signal TransducingAmino Acid Sequence
Animals
CD4-Positive T-Lymphocytes
Carrier Proteins
DNA-Binding Proteins
Detergents
Humans
Hybridomas
Isoenzymes
Jurkat Cells
*Membrane Proteins
Mice
Molecular Sequence Data
NFATC Transcription Factors
*Nuclear Proteins
Phospholipase C gamma
Phosphoproteins
Phosphorylation
Protein Conformation
Protein-Tyrosine Kinases
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
Sequence Homology, Amino Acid
*Signal Transduction
Time Factors
Transcription Factors
Type C Phospholipases
src Homology Domains
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Itk, a Tec family tyrosine kinase, acts downstream of Lck and phosphatidylinositol 3'-kinase to facilitate T cell receptor (TCR)-dependent calcium influxes and increases in extracellular-regulated kinase activity. Here we demonstrate interactions between Itk and crucial components of TCR-dependent signaling pathways. First, the inositide-binding pocket of the Itk pleckstrin homology domain directs the constitutive association of Itk with buoyant membranes that are the primary site of TCR activation and are enriched in both Lck and LAT. This association is required for the transphosphorylation of Itk. Second, the Itk proline-rich region binds to Grb2 and LAT. Third, the Itk Src homology (SH3) 3 and SH2 domains interact cooperatively with Syk-phosphorylated SLP-76. Notably, SLP-76 contains a predicted binding motif for the Itk SH2 domain and binds to full-length Itk in vitro. Finally, we show that kinase-inactive Itk can antagonize the SLP-76-dependent activation of NF-AT. The inhibition of NF-AT activation depends on the Itk pleckstrin homology domain, proline-rich region, and SH2 domain. Together, these observations suggest that multivalent interactions recruit Itk to LAT-nucleated signaling complexes and facilitate the activation of LAT-associated phospholipase Cgamma1 by Itk.Source
J Biol Chem. 2000 Jan 21;275(3):2219-30.
DOI
10.1074/jbc.275.3.2219Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42410PubMed ID
10636929Related Resources
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.275.3.2219
Scopus Count
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