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 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).
Ambach
A
A
Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany.
Saunus
J
J
Konstandin
M
M
Wesselborg
S
S
Meuer
S C
SC
Samstag
Y
Y
D051339:Actin Depolymerizing Factors; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008840:Microfilament Proteins / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology
D051339:Actin Depolymerizing Factors; D007555:Isoxazoles; D008840:Microfilament Proteins; D019319:Okadaic Acid; D003907:Dexamethasone; D016572:Cyclosporine; D010749:Phosphoprotein Phosphatases; D000077339:Leflunomide; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus