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

Cofilin, an actin-depolymerizing protein, is essential for the functional d ynamics of the actin cytoskeleton and for cell viability. In unstimulated h uman peripheral blood T lymphocytes cofilin is phosphorylated and localized in the cytoplasm. Following cc-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 a ctin-binding activity of cofilin are regulated by the phosphorylation stale of serine-3. Thus, only the dephosphorylated form of cofilin associates wi th 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 L IM-kinase 1: the serine/threonine phosphatases of type 1 and type 2A not on ly associate with cofilin but also dephosphorylate this 19-kDa protein and thereby mediate cofilin activation. In malignant T lymphoma cells, activati on of these phosphatases occurs spontaneously, independent of external stim uli. In untransformed human peripheral brood T lymphocytes, these phosphata ses function through a cyclosporin A/FK506-resistant co-stimulatory signali ng pathway which is common for the accessory receptors CD2 and CD28. This c ostimulatory signaling pathway is also not affected by a series of other cl inically established immunosuppressive drugs (i.e. rapamycin, dexamethasone , leflunomide or mycophenolic acid).