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Dr. Martha Cyert directs a research lab that studies Ca2+-dependent signal transduction, focusing on calcineurin, the highly conserved Ca2+/calmodulin-regulated protein phosphatase that plays critical roles in muscle, immune and neural cells. Dr. Cyert pioneered studies of yeast calcineurin, where her work elucidated conserved aspects of substrate recognition and mechanisms by which the signaling network evolves. Her studies on human calcineurin uncovered the mechanism by which immunosuppressant drugs, FK506 and cyclosporine A, inhibit this enzyme. More recently, her lab established the human calcineurin signaling network, using both experimental and computational approaches, which uncovered many new functions and substrates for calcineurin, including a conserved role in regulating nuclear transport via the nuclear pore complex. Professor Cyert is also an active educator. She received the Stanford Biosciences Excellence in Mentoring award, developed an innovative, inquiry-based, introductory laboratory course for undergraduates that examines p53, and initiated a summer transition program for incoming freshman from under resourced schools. She directed an NIH-funded graduate training program in Cell and Molecular Biology (2009-2019), and was an instructor for Cell Biology workshops in Ghana that were sponsored by the ASCB. Her administrative roles include serving as Senior Associate Vice Provost for Undergraduate Education from 2010-13, and Associate Chair of the Biology department (2014-2020), where she is now Chair. Dr. Cyert is a member of the Stanford Cardiovascular and Bio-X Institutes and plays leadership roles at the American Society for Biochemistry and Molecular Biology (ASBMB). She has been awarded fellowships from the American Cancer Society, the Life Sciences Research Foundation and the Lucille P. Markey Charitable Trust, and was named by Stanford University as a Terman Fellow, a Gabilan Fellow, and as the Thomas W. and Susan B. Ford University Fellow in Undergraduate Education.
American Society for Cell Biology
1. MAPPING THE HUMAN CALCINEURIN PHOSPHATASE SIGNALING NETWORK THROUGH GLOBAL IDENTIFICATION OF SHORT LINEAR MOTIFS THAT MEDIATE SUBSTRATE RECOGNITION. Systems-level analyses of phosphorylation-based signaling networks has transformed our understanding of kinase function, but knowledge of phosphatase signaling has lagged behind, primarily because global approaches to identify phosphatase substrates are lacking. Calcineurin, the conserved Ca2+/calmodulin-dependent protein phosphatase and target of immunosuppressants, FK506 and Cyclosporin A, is ubiquitously expressed, and critically regulates Ca2+-dependent processes in the immune system, heart, and brain. However, in the literature only ~70 substrates are attributed to calcineurin. Systematic identification of calcineurin targets is now feasible due to insights into its conserved mechanism of substrate recognition. Calcineurin acts on phosphosites with little primary sequence similarity; thus specificity is not encoded within regions contiguous to the phosphosite. Rather, the enzyme binds to short linear motifs (SLiMs),“PxIxIT” and “LxVP”, which can occur hundreds of residues away from dephosphorylation sites. CsA , FK506 and the viral A238L protein inhibit calcineurin by blocking SLiM binding to conserved surfaces on the enzyme. SLiMs are a growing class of sequences that localize within intrinsically disordered regions, i.e. flexible protein domains that lack a defined structure. SLiMs mediate most protein-protein interactions in cells and evolve rapidly to mediate rewiring of signaling networks, including that of calcineurin. However, degenerate sequences and low affinities for their target domains make SLiMs challenging to identify. We are using novel experimental and computational approaches to identify calcineurin-binding SLiMs systematically in the human proteome. Calcineurin-binding sequences of the PxIxIT and LxVP types were identified from the human proteome using phage display, and this large collection of sequences allowed us to develop robust strategies to identify these SLiMs in silico. Also, using proximity-dependent biotinylation we identified calcineurin proximal proteins at the centrosome and nuclear pore complex (NPC). These systematic approaches led us to identify conserved regulation of NPC proteins and nuclear transport by calcineurin, and we are continuing to discover global functions for this phosphatase in humans.2. FUNCTIONAL STUDIES OF HUMAN CNAβ1 SPLICE VARIANT Calcineurin is tightly controlled by Ca2+ and calmodulin, which activate the enzyme by relieving auto-inhibition of the active site, and revealing a critical binding pocket for "LxVP" substrate motifs. We are studying a conserved splice variant of the human CNAβ gene, CNAβ1, which promotes cardiac regeneration in vivo. CNAβ1 has distinct enzymatic properties, and associates with membranes via conserved sites of palmitoylation in its C-terminus. Functional studies are identifying and characterizing unique protein partners for CNAβ1 and its substrates in cardiovascular and endocrine signaling. Specifically, our studies establish roles for CNAβ1 in regulating phosphoinositide signaling during activation of G-protein couple receptors (GPCRs).