Phostensin Enables Lymphocyte Integrin Activation and Population of Peripheral Lymphoid Organs
Rap1 GTPase drives assembly of the Mig10/RIAM/lamellipodin–Integrin–Talin (MIT) complex that enables integrin dependent lymphocyte functions. Here we used tandem affinity tag based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (PTSN), a regulatory subunit of protein phosphatase 1, is a component of the complex. PTSN mediates dephosphorylation of Rap1 thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes PTSN, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18 null mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable to defective activation of integrins. Ppp1r18 null T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, PTSN enables lymphocyte integrin mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of PTSN ameliorates T cell mediated colitis.