RT Journal Article SR Electronic T1 Closed Loop Control between Two GTPase Switches makes the Secretory Functions of the Golgi Responsive to Growth Factors JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.18.436048 DO 10.1101/2021.03.18.436048 A1 Lingxia Qiao A1 I-Chung Lo A1 Krishna K. Midde A1 Nicolas Aznar A1 Amer Ali Abd El-Hafeez A1 Inmaculada Lopez-Sanchez A1 Vijay Gupta A1 Marilyn G. Farquhar A1 Padmini Rangamani A1 Pradipta Ghosh YR 2021 UL http://biorxiv.org/content/early/2021/03/19/2021.03.18.436048.abstract AB Intercellular (between-cells) signals must be converted into an intracellular (within-cell) signal before it can trigger a proportionate response. How cells mount such proportionate responses within their interior remains unknown. Here we unravel the role of a coupled GTPase circuit on the Golgi membranes which enables the intracellular secretory machinery to respond proportionately to the growth factors in the extracellular space. The circuit, comprised of two species of biological switches, the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase, Giαβγ and their corresponding GAPs and GEFs, is coupled via at least one a forward and two key negative feedback loops. Interrogation of the circuit featuring such closed-loop control (CLC) using an integrated systems-based and experimental approach showed that CLC allows the two GTPases to mutually control each other and convert the expected switch-like behavior of Arf1 into an unexpected dose response aligned (DoRA) linear behavior. Such behavior translates into growth factor stimulated Giαβγ activity on Golgi membranes, temporal finiteness of Arf1 activity, and cellular secretion that is proportional to the stimuli. Findings reveal the importance of the coupled GTPase circuit in rendering concordant cellular responses via the faithful transmission of growth signals to the secretory machinery.HIGHLIGHTSEndo- (mono) and ectomembrane (trimeric) GTPase systems are believed to function independently.Their coupling in a closed loop system at the Golgi makes cell secretion proportionate to stimuli.Coupling enables closed-loop mutual control of both GTPases and dose response alignment (DoRA).Uncoupling creates an open loop which generates misaligned and discordant responses.Competing Interest StatementThe authors have declared no competing interest.GIVGα-interacting Vesicle-associated proteinGEMguanine nucleotide exchange modulatorDoRAdose-response alignmentArf1ADP-ribosylation factor-1EGFEpidermal growth factorERendoplasmic reticulumERGICER-Golgi Intermediate CompartmentCLCclosed loop controlGGAGolgi-localized,γ-ear-containingArf-binding protein