We discover and elucidate new Ca2+-regulated signaling pathways in humans by studying calcineurin, the conserved Ca2+/calmodulin-regulated protein phosphatase. The calcineurin phosphatase dephosphorylates proteins only when Ca2+ signaling is triggered, for example by a hormone, growth factor, neurotransmitter etc. Previous work from the Cyert lab showed how calcineurin allows yeast cells to survive environmental stress (Goldman et al, 2014, Molecular Cell). Currently, we are studying human calcineurin which is ubiquitously expressed and plays critical roles throughout the body, but especially in the nervous, cardiac and immune systems. Calcineurin is best known for activating the adaptive immune response by dephosphorylating the NFAT transcription factors, and is the target of widely prescribed immunosuppressant drugs, FK506 (tacrolimus) and Cyclosporin A. However, these drugs cause many adverse effects due to inhibition of calcineurin in non-immune tissues, where the majority of calcineurin substrates and functions remain to be discovered. We are using a variety of experimental and computational strategies to systematically map human calcineurin signaling pathways in healthy and diseased cells. These rely on identifying Short Linear peptide Motif (SLiMs), i.e. highly variable sequences that reside in regions of intrinsic disorder and mediate specific interactions of substrates and regulators with calcineurin. These approaches have revealed surprising roles for calcineurin that we are currently studying: in Notch signaling, trafficking though nuclear pores, at centrosomes/cilia, and in regulating phosphoinositide signaling at membranes. A new project is studying calcineurin's role in pancreatitis, where we are identifying calcineurin substrates that mediate the major pathophysiological events that occur during pancreatitis. We are also interested in understanding how reversible protein lipidation (palmitoylation) is regulated and how palmitoylation impacts calcineurin signaling at membranes by modifying calcineurin itself and some of its regulators.
To learn more about our studies, see our recent papers: Wigington, Roy et al, 2020, Molecular Cell (https://pubmed.ncbi.nlm.nih.gov/32645368/) and Ulengin-Talkish et al, Nature Communications (https://www.nature.com/articles/s41467-021-26326-4).
