Closed-Loop Control between Two GTPase Switches makes the Secretory Functions of the Golgi Responsive to Growth Factors

Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cells ability to secrete-and-sense growth factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Gi{beta}{gamma} and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint growth factors (e.g., the epidermal growth factor; EGF) as a key stimuli for such self-sustenance. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors. SYNOPSIS IMAGE O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY STANDFIRST TEXTThis work defines the inner workings of a Golgi-localized molecular circuitry comprised of coupled GTPases, which empowers cells to achieve self-sufficiency in growth factor signaling by creating a secrete-and-sense autocrine loop. HIGHLIGHTS/MAIN FINDINGSO_LIModeling and experimental approaches were used to dissect a coupled GTPase circuit. C_LIO_LICoupling enables closed loop feedback and mutual control of GTPases. C_LIO_LICoupling generates dose response alignment behavior of sensing and secretion of growth factors. C_LIO_LICoupling is critical for multiscale feedback control to achieve secretion-coupled autonomy. C_LI