The serine phosphatases PP1 and PP2A associate with and activate the actin-binding protein cofilin in human T lymphocytes

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Abstract
Cofilin, an actin‐depolymerizing protein, is essential for the functional dynamics of the actin cytoskeleton and for cell viability. In unstimulated human peripheral blood T lymphocytes cofilin is phosphorylated and localized in the cytoplasm. Following co‐stimulation through accessory receptors (e.g. CD2 or CD28) – however, not following TCR/CD3 stimulation alone – cofilin undergoes dephosphorylation. The subcellular localization as well as the actin‐binding activity of cofilin are regulated by the phosphorylation state of serine‐3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM‐kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM‐kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19‐kDa protein and thereby mediate cofilin activation. In malignant T lymphoma cells, activation of these phosphatases occurs spontaneously, independent of external stimuli. In untransformed human peripheral blood T lymphocytes, these phosphatases function through a cyclosporin A/FK506‐resistant co‐stimulatory signaling pathway which is common for the accessory receptors CD2 and CD28. This co‐stimulatory signaling pathway is also not affected by a series of other clinically established immunosuppressive drugs (i.e. rapamycin, dexamethasone, leflunomide or mycophenolic acid).