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Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor.

ABSTRACT: Focal adhesion kinase (FAK) is a critical regulator of signal transduction in multiple cell types. Although this protein is activated upon TCR engagement, the cellular function that FAK plays in mature human T cells is unknown. By suppressing the function of FAK, we revealed that FAK inhibits TCR-mediated signaling by recruiting C-terminal Src kinase to the membrane and/or receptor complex following TCR activation. Thus, in the absence of FAK, the inhibitory phosphorylation of Lck and/or Fyn is impaired. Together, these data highlight a novel role for FAK as a negative regulator TCR function in human T cells. These results also suggest that changes in FAK expression could modulate sensitivity to TCR stimulation and contribute to the progression of T cell malignancies and autoimmune diseases.

SUBMITTER: Chapman NM

PROVIDER: S-EPMC3865716 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Focal adhesion kinase negatively regulates Lck function downstream of the T cell antigen receptor.

Chapman Nicole M NM Connolly Sean F SF Reinl Erin L EL Houtman Jon C D JC

Journal of immunology (Baltimore, Md. : 1950) 20131113 12

Focal adhesion kinase (FAK) is a critical regulator of signal transduction in multiple cell types. Although this protein is activated upon TCR engagement, the cellular function that FAK plays in mature human T cells is unknown. By suppressing the function of FAK, we revealed that FAK inhibits TCR-mediated signaling by recruiting C-terminal Src kinase to the membrane and/or receptor complex following TCR activation. Thus, in the absence of FAK, the inhibitory phosphorylation of Lck and/or Fyn is ...[more]

PMID: 24227778

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Focal Adhesion Kinase Dependent Expression

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The KDEL receptor signalling cascade targets focal adhesion kinase on focal adhesions and invadopodia.

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Project description:Src kinase is a crucial mediator of adhesion-related signaling and motility. Src binds to focal adhesion kinase (FAK) through its SH2 domain and subsequently activates it for phosphorylation of downstream substrates. In addition to this binding function, data suggested that the SH2 domain might also perform an important role in targeting Src to focal adhesions (FAs) to enable further substrate phosphorylations. To examine this, we engineered an R175L mutation in cSrc to prevent the interaction with FAK pY397. This constitutively open Src kinase mediated up-regulated substrate phosphorylation in SYF cells but was unable to promote malignant transformation. Significantly, SrcR175L cells also had a profound motility defect and an impaired FA generation capacity. Importantly, we were able to recapitulate wild-type motile behavior and FA formation by directing the kinase to FAs, clearly implicating the SH2 domain in recruitment to FAK and indicating that this targeting capacity, and not simply Src-FAK scaffolding, was critical for normal Src function.

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