Regulating cellular cyclic adenosine monophosphate: “Sources,” “sinks,” and now, “tunable valves”

Focus Article

Michael Getz, Padmini Rangamani, Pradipta Ghosh

Published Online: Apr 23 2020

DOI: 10.1002/wsbm.1490

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Abstract A number of hormones and growth factors stimulate target cells via the second messenger pathways, which in turn regulate cellular phenotypes. Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that facilitates numerous signal transduction pathways; its production in cells is tightly balanced by ligand‐stimulated receptors that activate adenylate cyclases (ACs), that is, “source” and by phosphodiesterases (PDEs) that hydrolyze it, that is, “sinks.” Because it regulates various cellular functions, including cell growth and differentiation, gene transcription and protein expression, the cAMP signaling pathway has been exploited for the treatment of numerous human diseases. Reduction in cAMP is achieved by blocking “sources”; however, elevation in cAMP is achieved by either stimulating “source” or blocking “sinks.” Here we discuss an alternative paradigm for the regulation of cellular cAMP via GIV/Girdin, the prototypical member of a family of modulators of trimeric GTPases, Guanine nucleotide Exchange Modulators (GEMs). Cells upregulate or downregulate cellular levels of GIV‐GEM, which modulates cellular cAMP via spatiotemporal mechanisms distinct from the two most often targeted classes of cAMP modulators, “sources” and “sinks.” A network‐based compartmental model for the paradigm of GEM‐facilitated cAMP signaling has recently revealed that GEMs such as GIV serve much like a “tunable valve” that cells may employ to finetune cellular levels of cAMP. Because dysregulated signaling via GIV and other GEMs has been implicated in multiple disease states, GEMs constitute a hitherto untapped class of targets that could be exploited for modulating aberrant cAMP signaling in disease states. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Cell Signaling

Schematic summarizing the unique impacts of GIV‐GEM on the EGFR→ cAMP pathway, as revealed by systems biology. Top: Within the “bow‐tie” microarchitecture of layered signal flow in any circuit, incoming signals from RTKs like EGFR (signal input; left) are integrated by core proteins like GIV (center) that activate second messengers like cAMP, which subsequently impacts multiple target proteins such as kinases, phosphatases, and transcription factors (output signals; right). Prior systems biology work had concluded that cellular concentrations of cAMP is a key determinant of robustness at the core of information (signal) flow (Doyle & Csete, 2011; Friedlander, Mayo, Tlusty, & Alon, 2015; Kirschner & Gerhart, 1998). While cAMP production is tuned up or down by variable levels of GIV and its compartmentalized action on Gai/Gas and ACs within the RTK‐cAMP pathway, cAMP degradation by PDEs serves as a dominant sink (drainpipe). Bottom: Within the hourglass microarchitecture for vertical flow of “control,” upregulation/downregulation of GIV‐GEM in cells serves as a tunable control valve, allowing cells to control cAMP production in cells responding to growth factors. When GIV‐GEM expression is low (as seen in the normal epithelium), increasing input signals can trigger some of the highest levels of cellular cAMP, thereby conferring sensitivity (left). Increasing GIV‐GEM expression throttles the cAMP response (middle), such that, when GIV‐GEM is expressed highly as seen across all cancers, cAMP levels remain low, regardless of the amount of input signals, thereby conferring robustness (right)

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An emerging paradigm for modulation of cellular cAMP by growth factors. (A) Schematic summarizing the role of cyclic AMP (cAMP) in diverse biological processes. In cancers (top right), cAMP is largely protective as it inhibits proliferation, invasion, chemoresistance, and promotes apoptosis and differentiation of tumor cells. Similarly, in the context of organ fibrosis, cAMP is a potent anti‐fibrotic agent because it inhibits proliferation and migration and triggers apoptosis and return to quiescence for myofibroblasts, the major cell type implicated in fibrogenic disorders. Red lines indicate suppression and green lines indicate promotion. Citations for each process can be found under the process images (K. C. Agarwal & Parks Jr, 1983; Bartels, Lee, & Neufeld, 1982; Caprioli & Sears, 1983; Cho‐Chung, 1990; Evans, 1986; Insel et al., 2012; Kramer, Thormann, Kindler, & Schlepper, 1987; Kreutner, Chapman, Gulbenkian, & Tozzi, 1985; Raker, Becker, & Steinbrink, 2016; Serezani, Ballinger, Aronoff, & Peters‐Golden, 2008; Silva, Kogan, Frankland, & Kida, 1998; Vitale, Dicitore, Mari, & Cavagnini, 2009; Wachtel & Löschmann, 1986)

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Schematic summarizing the diverse pathologic states that feature either too little or too much GIV. Because of its ability to serve as a tunable valve for cellular cAMP concentrations, too high or too low levels of expression of GIV may robustly regulate the tonic levels of cAMP in cells. Low GIV‐states are associated with high cAMP (top), high GIV‐states are associated with low cAMP (bottom). Text boxes on the right list pathophysiologic conditions associated with deregulated GIV and cAMP states (Table 1)

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