Research ArticleImmunology

Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1

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Sci. Signal.  11 Dec 2018:
Vol. 11, Issue 560, eaat3178
DOI: 10.1126/scisignal.aat3178

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Crk adapts integrins to T cell movement

Signaling by integrins on the cell surface of lymphocytes, such as T cells, upon interaction with proteins on the surface of endothelial cells facilitates lymphocytic adhesion to and migration through blood vessel walls during inflammatory responses. Cell movement involves coordinated changes to the cellular cytoskeleton. Roy et al. found that Crk family adaptor proteins were critical links in the pathways between the activated integrin LFA-1 and cytoskeletal rearrangements in T cells. Activated LFA-1 engaged Crk-associated complexes that enabled the activation of key regulators of actin polymerization and the formation of lamellipodia, projections that propelled the cells across various culture substrates. These findings uncover more of the mechanistic underpinnings of the migratory T cell response, which may enable future therapeutic control of this process in disease.

Abstract

T cell entry into inflamed tissue involves firm adhesion, spreading, and migration of the T cells across endothelial barriers. These events depend on “outside-in” signals through which engaged integrins direct cytoskeletal reorganization. We investigated the molecular events that mediate this process and found that T cells from mice lacking expression of the adaptor protein Crk exhibited defects in phenotypes induced by the integrin lymphocyte function–associated antigen 1 (LFA-1), namely, actin polymerization, leading edge formation, and two-dimensional cell migration. Crk protein was an essential mediator of LFA-1 signaling–induced phosphorylation of the E3 ubiquitin ligase c-Cbl and its subsequent interaction with the phosphatidylinositol 3-kinase (PI3K) subunit p85, thus promoting PI3K activity and cytoskeletal remodeling. In addition, we found that Crk proteins were required for T cells to respond to changes in substrate stiffness, as measured by alterations in cell spreading and differential phosphorylation of the force-sensitive protein CasL. These findings identify Crk proteins as key intermediates coupling LFA-1 signals to actin remodeling and provide mechanistic insights into how T cells sense and respond to substrate stiffness.

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