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Itk: the rheostat of the T cell response.

Grasis JA, Tsoukas CD - J Signal Transduct (2011)

Bottom Line: The functional cellular outcome of these molecular regulations by Itk renders it an important mediator of T cell development and differentiation.This paper encompasses the structure of Itk, the signaling parameters leading to Itk activation, and Itk effects on molecular pathways resulting in functional cellular outcomes.The incorporation of these factors persuades one to believe that Itk serves as a modulator, or rheostat, critically fine-tuning the T cell response.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, San Diego State University, San Diego, CA 92182-4614, USA.

ABSTRACT
The nonreceptor tyrosine kinase Itk plays a key role in TCR-initiated signaling that directly and significantly affects the regulation of PLCĪ³1 and the consequent mobilization of Ca(2+). Itk also participates in the regulation of cytoskeletal reorganization as well as cellular adhesion, which is necessary for a productive T cell response. The functional cellular outcome of these molecular regulations by Itk renders it an important mediator of T cell development and differentiation. This paper encompasses the structure of Itk, the signaling parameters leading to Itk activation, and Itk effects on molecular pathways resulting in functional cellular outcomes. The incorporation of these factors persuades one to believe that Itk serves as a modulator, or rheostat, critically fine-tuning the T cell response.

No MeSH data available.


Related in: MedlinePlus

Mode of Itk activation through the T cell receptor. While residing in the cytoplasm, Itk preferentially takes on an inhibited homodimer conformation and in some instances as an inhibited independent cis-conformation.  Upon T cell engagement, Itk is able to bind SLP-76 through its SH3 domain and shuttled to the LAT signalosome.  Once there, activated ZAP-70 phosphorylates SLP-76 on tyrosine 145 which Itk then binds to with its SH2 domain to solidify the connection at the signalosome.  At which time Itk localizes to the plasma membrane by binding PI3K-generated PIP3 with its PH domain and Itk then becomes tyrosine phosphorylated by Lck on tyrosine 511.  This leads to Itk's catalytic activity that first phosphorylates itself on tyrosine 180 culminating in a fully activated enzyme.
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fig2: Mode of Itk activation through the T cell receptor. While residing in the cytoplasm, Itk preferentially takes on an inhibited homodimer conformation and in some instances as an inhibited independent cis-conformation. Upon T cell engagement, Itk is able to bind SLP-76 through its SH3 domain and shuttled to the LAT signalosome. Once there, activated ZAP-70 phosphorylates SLP-76 on tyrosine 145 which Itk then binds to with its SH2 domain to solidify the connection at the signalosome. At which time Itk localizes to the plasma membrane by binding PI3K-generated PIP3 with its PH domain and Itk then becomes tyrosine phosphorylated by Lck on tyrosine 511. This leads to Itk's catalytic activity that first phosphorylates itself on tyrosine 180 culminating in a fully activated enzyme.

Mentions: The activation of Itk is a complex orchestration of events (Figure 2). This kinase is activated through a myriad of surface receptors, including the TCR/CD3 signaling complex, co-receptors, chemokine receptors, and heterotrimeric G-protein-coupled receptors (GPCRs). Prior to the activation of the T cell, Itk resides in the cytoplasm in a closed, autoinhibited state. This inhibitory conformation occurs through the cisbinding of its SH3 domain to the PRR of the TH domain [51]. More recently, however, it was found that the SH2 and SH3 domains of Itk could dimerize with each other in a trans-head-to-tail manner that could preclude or mitigate the cis-binding of a single Itk molecule to itself [73]. Further, it was found that full-length Itk self-associates intermolecularly [74]. This intermolecular clustering negatively regulates Itk and, once disrupted, leads to Itk activity. Continuing to determine the conformational state and activation of full-length Itk is of critical importance, as the information will be utilized for inhibitor development.


Itk: the rheostat of the T cell response.

Grasis JA, Tsoukas CD - J Signal Transduct (2011)

Mode of Itk activation through the T cell receptor. While residing in the cytoplasm, Itk preferentially takes on an inhibited homodimer conformation and in some instances as an inhibited independent cis-conformation.  Upon T cell engagement, Itk is able to bind SLP-76 through its SH3 domain and shuttled to the LAT signalosome.  Once there, activated ZAP-70 phosphorylates SLP-76 on tyrosine 145 which Itk then binds to with its SH2 domain to solidify the connection at the signalosome.  At which time Itk localizes to the plasma membrane by binding PI3K-generated PIP3 with its PH domain and Itk then becomes tyrosine phosphorylated by Lck on tyrosine 511.  This leads to Itk's catalytic activity that first phosphorylates itself on tyrosine 180 culminating in a fully activated enzyme.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3116522&req=5

fig2: Mode of Itk activation through the T cell receptor. While residing in the cytoplasm, Itk preferentially takes on an inhibited homodimer conformation and in some instances as an inhibited independent cis-conformation. Upon T cell engagement, Itk is able to bind SLP-76 through its SH3 domain and shuttled to the LAT signalosome. Once there, activated ZAP-70 phosphorylates SLP-76 on tyrosine 145 which Itk then binds to with its SH2 domain to solidify the connection at the signalosome. At which time Itk localizes to the plasma membrane by binding PI3K-generated PIP3 with its PH domain and Itk then becomes tyrosine phosphorylated by Lck on tyrosine 511. This leads to Itk's catalytic activity that first phosphorylates itself on tyrosine 180 culminating in a fully activated enzyme.
Mentions: The activation of Itk is a complex orchestration of events (Figure 2). This kinase is activated through a myriad of surface receptors, including the TCR/CD3 signaling complex, co-receptors, chemokine receptors, and heterotrimeric G-protein-coupled receptors (GPCRs). Prior to the activation of the T cell, Itk resides in the cytoplasm in a closed, autoinhibited state. This inhibitory conformation occurs through the cisbinding of its SH3 domain to the PRR of the TH domain [51]. More recently, however, it was found that the SH2 and SH3 domains of Itk could dimerize with each other in a trans-head-to-tail manner that could preclude or mitigate the cis-binding of a single Itk molecule to itself [73]. Further, it was found that full-length Itk self-associates intermolecularly [74]. This intermolecular clustering negatively regulates Itk and, once disrupted, leads to Itk activity. Continuing to determine the conformational state and activation of full-length Itk is of critical importance, as the information will be utilized for inhibitor development.

Bottom Line: The functional cellular outcome of these molecular regulations by Itk renders it an important mediator of T cell development and differentiation.This paper encompasses the structure of Itk, the signaling parameters leading to Itk activation, and Itk effects on molecular pathways resulting in functional cellular outcomes.The incorporation of these factors persuades one to believe that Itk serves as a modulator, or rheostat, critically fine-tuning the T cell response.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, San Diego State University, San Diego, CA 92182-4614, USA.

ABSTRACT
The nonreceptor tyrosine kinase Itk plays a key role in TCR-initiated signaling that directly and significantly affects the regulation of PLCĪ³1 and the consequent mobilization of Ca(2+). Itk also participates in the regulation of cytoskeletal reorganization as well as cellular adhesion, which is necessary for a productive T cell response. The functional cellular outcome of these molecular regulations by Itk renders it an important mediator of T cell development and differentiation. This paper encompasses the structure of Itk, the signaling parameters leading to Itk activation, and Itk effects on molecular pathways resulting in functional cellular outcomes. The incorporation of these factors persuades one to believe that Itk serves as a modulator, or rheostat, critically fine-tuning the T cell response.

No MeSH data available.


Related in: MedlinePlus