A cellular atlas of calcineurin signaling

Intracellular Ca2+ signals are temporally controlled and spatially restricted. Signaling occurs adjacent to sites of Ca2+ entry and/or release, where Ca2+-dependent effectors and their substrates co-localize to form signaling microdomains. Here we review signaling by calcineurin, the Ca2+/calmodulin regulated protein phosphatase and target of immunosuppressant drugs, Cyclosporin A and FK506. Although well known for its activation of the adaptive immune response via NFAT dephosphorylation, systematic mapping of human calcineurin substrates and regulators reveals unexpected roles for this versatile phosphatase throughout the cell. We discuss calcineurin function, with an emphasis on where signaling occurs and mechanisms that target calcineurin and its substrates to signaling microdomains, especially binding of cognate short linear peptide motifs (SLiMs). Calcineurin is ubiquitously expressed and regulates events at the plasma membrane, other intracellular membranes, mitochondria, the nuclear pore complex and centrosomes/cilia. Based on our expanding knowledge of localized CN actions, we describe a cellular atlas of Ca2+/calcineurin signaling.