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Mol Cell

Title:		CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5
Author(s):		Repetto MV; Winters MJ; Bush A; Reiter W; Hollenstein DM; Ammerer G; Pryciak PM; Colman-Lerner A;
Address:		"Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), C1428EGA Buenos Aires, Argentina; CONICET-UBA, Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE), Buenos Aires C1428EHA, Argentina. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Department for Biochemistry, Max F. Perutz Laboratories, University of Vienna, Vienna 1030, Austria. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: peter.pryciak@umassmed.edu. Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), C1428EGA Buenos Aires, Argentina; CONICET-UBA, Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE), Buenos Aires C1428EHA, Argentina. Electronic address: colman-lerner@fbmc.fcen.uba.ar"
Journal Title:		Mol Cell
Year:		2018
Volume:		69
Issue:		6
Page Number:		938 - 952
DOI:		10.1016/j.molcel.2018.02.018
ISSN/ISBN:		1097-4164 (Electronic) 1097-2765 (Print) 1097-2765 (Linking)
Abstract:		"We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages. Surprisingly, in S phase, where Ste5 recruitment should be blocked, we observed an initial recruitment followed by a steep drop-off. This delayed inhibition revealed a requirement for both CDK activity and negative feedback from the pathway MAPK Fus3. Mutagenesis, mass spectrometry, and electrophoretic analyses suggest that the CDK and MAPK modify shared sites, which are most extensively phosphorylated when both kinases are active and able to bind their docking sites on Ste5. Such collaborative phosphorylation can broaden regulatory inputs and diversify output dynamics of signaling pathways"
Keywords:		"Adaptor Proteins, Signal Transducing/genetics/*metabolism Binding Sites Cell Cycle Checkpoints Cell Membrane/enzymology Cyclin-Dependent Kinases/genetics/*metabolism Cyclins/genetics/metabolism Kinetics Mitogen-Activated Protein Kinases/genetics/*metaboli;"
Notes:		"MedlineRepetto, Maria Victoria Winters, Matthew J Bush, Alan Reiter, Wolfgang Hollenstein, David Maria Ammerer, Gustav Pryciak, Peter M Colman-Lerner, Alejandro eng R01 GM057769/GM/NIGMS NIH HHS/ R01 GM097479/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2018/03/17 Mol Cell. 2018 Mar 15; 69(6):938-952.e6. doi: 10.1016/j.molcel.2018.02.018"