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Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT
WL. Lo, NH. Shah, N. Ahsan, V. Horkova, O. Stepanek, AR. Salomon, J. Kuriyan, A. Weiss,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P01 AI091580
NIAID NIH HHS - United States
P30 DK063720
NIDDK NIH HHS - United States
P30 GM110759
NIGMS NIH HHS - United States
R01 AI083636
NIAID NIH HHS - United States
NLK
ProQuest Central
from 2000-07-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-07-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-07-01 to 1 year ago
- MeSH
- Adaptor Proteins, Signal Transducing chemistry metabolism MeSH
- Amino Acid Motifs MeSH
- Phosphorylation MeSH
- HEK293 Cells MeSH
- Jurkat Cells MeSH
- Humans MeSH
- Membrane Proteins chemistry metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Proline analysis MeSH
- ZAP-70 Protein-Tyrosine Kinase metabolism MeSH
- Receptors, Antigen, T-Cell metabolism MeSH
- Thymus Gland immunology MeSH
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.
Departments of Molecular and Cell Biology University of California Berkeley Berkeley CA USA
Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic
References provided by Crossref.org
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- $a T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.
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