An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor

Shah, Neel H.; Wang, Qi; Yan, Qingrong; Karandur, Deepti; Kadlecek, Theresa A.; Fallahee, Ian; Russ, William P.; Ranganathan, Rama; Weiss, Arthur; Kuriyan, John

doi:10.7554/elife.20105

Cited by 90 publications

(207 citation statements)

References 96 publications

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“…2 also supported the notion that CD3e BRS is functionally more important than PRS in mediating CD3 phosphorylation. Note that the interaction between ITAM and Lck kinase is also important for determining CD3 phosphorylation (26).…”

Section: Discussionmentioning

confidence: 99%

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Ionic CD3−Lck interaction regulates the initiation of T-cell receptor signaling

Guo

Shi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Antigen-triggered T-cell receptor (TCR) phosphorylation is the first signaling event in T cells to elicit adaptive immunity against invading pathogens and tumor cells. Despite its physiological importance, the underlying mechanism of TCR phosphorylation remains elusive. Here, we report a key mechanism regulating the initiation of TCR phosphorylation. The major TCR kinase Lck shows high selectivity on the four CD3 signaling proteins of TCR. CD3e is the only CD3 chain that can efficiently interact with Lck, mainly through the ionic interactions between CD3e basic residue-rich sequence (BRS) and acidic residues in the Unique domain of Lck. We applied a TCR reconstitution system to explicitly study the initiation of TCR phosphorylation. The ionic CD3e−Lck interaction controls the phosphorylation level of the whole TCR upon antigen stimulation. CD3e BRS is sequestered in the membrane, and antigen stimulation can unlock this motif. Dynamic opening of CD3e BRS and its subsequent recruitment of Lck thus can serve as an important switch of the initiation of TCR phosphorylation.T-cell receptor | Lck | initial phosphorylation | substrate selectivity | ionic interaction

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Section: Discussionmentioning

confidence: 99%

“…This earliest event of TCR signaling is crucial because it determines the downstream signaling programs. More recently, residues surrounding ITAM tyrosines have been found to be important for interaction with the Lck kinase domain and affect substrate selectivity of Lck (26). Whether other Lck domains contribute to CD3 selectivity is still unclear.…”

mentioning

confidence: 99%

Ionic CD3−Lck interaction regulates the initiation of T-cell receptor signaling

Guo

Shi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, available motifs in the literature agree with the motifs obtained in our approach. For example a strong preference for a proline at the +3 position for ABL2 is recapitulated (Colicelli, 2010;Wagih et al, 2015) (Figure 3a) as well as a preference for acidic amino acids (D and E) at the -3 position for SRC kinase (Songyang and Cantley, 1995) or the preference for aspartic acid at the -1 position for SYK (Deng et al, 2014;Shah et al, 2016) (Suppl. Figure 2).…”

Section: Linear Sequence Motif Analysismentioning

confidence: 96%

Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate

et al. 2017

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Systematic assessment of tyrosine kinase-substrate relationships is fundamental to a better understanding of cellular signaling and its profound alterations in human diseases such as cancer. In human cells, complex signaling networks, feedback loops, conditional activity and intra-kinase redundancy combine to confound systematic attempts to address this topic. We leveraged the model organism S. cerevisiae to individually express human non-receptor tyrosine kinases (NRTKs) and exploited the full yeast proteome as an in vivo model substrate. For 16 NRTKs, we recorded 3,279 kinase-substrate relationships involving 1,351 yeast pY-sites. From this data we generated a set of new linear kinase motifs and assigned ~1,300 known human pY-sites to specific NRTKs. Furthermore, experimentally defined pY-sites for each individual kinase were shown to cluster within the yeast interactome network irrespective of linear motif information. We therefore applied a network inference approach to predict kinase-substrate relationships for more than 3,500 human proteins, marking a substantial step forward in our understanding of kinase biology.. Corwin et al., revised3 7/25/2017 3

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“…The pair-correlation function of LAT clustering decays to 0 at a distance of 200 nm, but is half its maximum value at ~ 40 nm 3 . The ability of ZAP70 to trans auto-phosphorylate sites in LAT involves electrostatic attraction that may further enhance inter-digitation of the cytoplasmic domains of TCR and LAT once they are within ~ 40 nm 31 . CD45 exclusion on 3D surfaces was not detected within the limits of our measurement (Fig.…”

Section: Ligand Spacing and Kinetic Segregationmentioning

confidence: 99%

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

et al. 2018

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Elucidating the rules for receptor triggering in cell-cell and cell-matrix contacts requires precise control of ligand positioning in three dimensions. Here, we use the T cell receptor (TCR) as a model and subject T cells to different geometric arrangements of ligands, using a nanofabricated single-molecule array platform. This is comprised of monovalent TCR ligands anchored to lithographically patterned nanoparticle clusters surrounded by mobile adhesion molecules on a supported lipid bilayer (SLB). The TCR ligand could be co-planar with the SLB (2D), excluding the CD45 transmembrane tyrosine phosphatase, or elevated by 10 nm on solid nanopedestals (3D), allowing closer access of CD45 to engaged TCR. The two configurations resulted in different T cell responses, depending on the lateral spacing between the ligands. These results identify the important contributions of lateral and axial components of ligand positioning and create a more complete foundation for receptor engineering for immunotherapy.

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An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor

Cited by 90 publications

References 96 publications

Ionic CD3−Lck interaction regulates the initiation of T-cell receptor signaling

Ionic CD3−Lck interaction regulates the initiation of T-cell receptor signaling

Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

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