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

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

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

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)

[ Normal View | Magnified View ]

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)

[ Normal View | Magnified View ]

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)

[ Normal View | Magnified View ]

References

Agarwal,, K. C., & Parks,, R. E., Jr. (1983). Forskolin: A potential antimetastatic agent. International Journal of Cancer, 32(6), 801–804. https://doi.org/10.1002/ijc.2910320622
Agarwal,, S. R., Clancy,, C. E., & Harvey,, R. D. (2016). Mechanisms restricting diffusion of intracellular cAMP. Scientific Reports, 6, 19577. https://doi.org/10.1038/srep19577
Alenghat,, F. J., Tytell,, J. D., Thodeti,, C. K., Derrien,, A., & Ingber,, D. E. (2009). Mechanical control of cAMP signaling through integrins is mediated by the heterotrimeric Gαs protein. Journal of Cellular Biochemistry, 106(4), 529–538. https://doi.org/10.1002/jcb.22001
Amit,, I., Wides,, R., & Yarden,, Y. (2007). Evolvable signaling networks of receptor tyrosine kinases: Relevance of robustness to malignancy and to cancer therapy. Molecular Systems Biology, 3, 151. https://doi.org/10.1038/msb4100195
Anai,, M., Shojima,, N., Katagiri,, H., Ogihara,, T., Sakoda,, H., Onishi,, Y., … Asano,, T. (2005). A novel protein kinase B (PKB)/AKT‐binding protein enhances PKB kinase activity and regulates DNA synthesis. The Journal of Biological Chemistry, 280(18), 18525–18535. https://doi.org/10.1074/jbc.M500586200
Aznar,, N., Kalogriopoulos,, N., Midde,, K. K., & Ghosh,, P. (2016). Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 38(4), 379–393. https://doi.org/10.1002/bies.201500133
Aznar,, N., Midde,, K. K., Dunkel,, Y., Lopez‐Sanchez,, I., Pavlova,, Y., Marivin,, A., … Ghosh,, P. (2015). Daple is a novel non‐receptor GEF required for trimeric G protein activation in Wnt signaling. eLife, 4, e07091. https://doi.org/10.7554/eLife.07091
Barone,, I., Giordano,, C., Bonofiglio,, D., Andò,, S., & Catalano,, S. (2017). Phosphodiesterase type 5 and cancers: Progress and challenges. Oncotarget, 8(58), 99179–99202. https://doi.org/10.18632/oncotarget.21837
Bartels,, S. P., Lee,, S. R., & Neufeld,, A. H. (1982). Forskolin stimulates cyclic AMP synthesis, lowers intraocular pressure and increases outflow facility in rabbits. Current Eye Research, 2(10), 673–681. https://doi.org/10.3109/02713688209019996
Beas,, A. O., Taupin,, V., Teodorof,, C., Nguyen,, L. T., Garcia‐Marcos,, M., & Farquhar,, M. G. (2012). Gαs promotes EEA1 endosome maturation and shuts down proliferative signaling through interaction with GIV (Girdin). Molecular Biology of the Cell, 23(23), 4623–4634. https://doi.org/10.1091/mbc.E12-02-0133
Beavo,, J. A., & Brunton,, L. L. (2002). Cyclic nucleotide research—Still expanding after half a century. Nature Reviews. Molecular Cell Biology, 3(9), 710–718. https://doi.org/10.1038/nrm911
Bender,, A. T., & Beavo,, J. A. (2006). Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacological Reviews, 58(3), 488–520. https://doi.org/10.1124/pr.58.3.5
Bornheimer,, S. J., Maurya,, M. R., Farquhar,, M. G., & Subramaniam,, S. (2004). Computational modeling reveals how interplay between components of a GTPase‐cycle module regulates signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 101(45), 15899–15904. https://doi.org/10.1073/pnas.0407009101
Boucher,, M. J., Duchesne,, C., Lainé,, J., Morisset,, J., & Rivard,, N. (2001). CAMP protection of pancreatic cancer cells against apoptosis induced by ERK inhibition. Biochemical and Biophysical Research Communications, 285(2), 207–216. https://doi.org/10.1006/bbrc.2001.5147
Burke,, P., Schooler,, K., & Wiley,, H. S. (2001). Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Molecular Biology of the Cell, 12(6), 1897–1910.
Caprioli,, J., & Sears,, M. (1983). Forskolin lowers intraocular pressure in rabbits, monkeys, and man. Lancet (London, England), 1(8331), 958–960. https://doi.org/10.1016/s0140-6736(83)92084-6
Castro,, L. R. V., Gervasi,, N., Guiot,, E., Cavellini,, L., Nikolaev,, V. O., Paupardin‐Tritsch,, D., & Vincent,, P. (2010). Type 4 Phosphodiesterase plays different integrating roles in different cellular domains in pyramidal cortical neurons. The Journal of Neuroscience, 30(17), 6143–6151. https://doi.org/10.1523/JNEUROSCI.5851-09.2010
Chai,, S.‐P., & Fong,, J. C. (2015). Synergistic induction of insulin resistance by endothelin‐1 and cAMP in 3T3‐L1 adipocytes. Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1852(10, Part A), 2048–2055. https://doi.org/10.1016/j.bbadis.2015.06.026
Cho‐Chung,, Y. S. (1990). Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: New approaches to therapy. Cancer Research, 50(22), 7093–7100.
Coleman,, B. D., Marivin,, A., Parag‐Sharma,, K., DiGiacomo,, V., Kim,, S., Pepper,, J. S., … Garcia‐Marcos,, M. (2016). Evolutionary conservation of a GPCR‐independent mechanism of Trimeric G protein activation. Molecular Biology and Evolution, 33(3), 820–837. https://doi.org/10.1093/molbev/msv336
Doyle,, J. C., & Csete,, M. (2011). Architecture, constraints, and behavior. Proceedings of the National Academy of Sciences of the United States of America, 108(Supplement 3), 15624–15630. https://doi.org/10.1073/pnas.1103557108
Dumaz,, N., Hayward,, R., Martin,, J., Ogilvie,, L., Hedley,, D., Curtin,, J. A., … Marais,, R. (2006). In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Research, 66(19), 9483–9491. https://doi.org/10.1158/0008-5472.CAN-05-4227
Enomoto,, A., Murakami,, H., Asai,, N., Morone,, N., Watanabe,, T., Kawai,, K., … Takahashi,, M. (2005). Akt/PKB regulates Actin organization and cell motility via Girdin/APE. Developmental Cell, 9(3), 389–402. https://doi.org/10.1016/j.devcel.2005.08.001
Erion,, D. M., Ignatova,, I. D., Yonemitsu,, S., Nagai,, Y., Chatterjee,, P., Weismann,, D., … Shulman,, G. I. (2009). Prevention of hepatic Steatosis and hepatic insulin resistance by knockdown of cAMP response element‐binding protein. Cell Metabolism, 10(6), 499–506. https://doi.org/10.1016/j.cmet.2009.10.007
Evans,, D. B. (1986). Modulation of cAMP: Mechanism for positive inotropic action. Journal of Cardiovascular Pharmacology, 8(Suppl 9), S22–S29.
Fajardo,, A. M., Piazza,, G. A., & Tinsley,, H. N. (2014). The role of cyclic nucleotide signaling pathways in cancer: Targets for prevention and treatment. Cancers, 6(1), 436–458. https://doi.org/10.3390/cancers6010436
Filmore,, D. (2004). It`s a GPCR world. Modern Drug Discovery, 7(11), 24–28.
Follin‐Arbelet,, V., Hofgaard,, P. O., Hauglin,, H., Naderi,, S., Sundan,, A., Blomhoff,, R., … Blomhoff,, H. K. (2011). Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model. BMC Cancer, 11(1), 301. https://doi.org/10.1186/1471-2407-11-301
Friedlander,, T., Mayo,, A. E., Tlusty,, T., & Alon,, U. (2015). Evolution of bow‐tie architectures in biology. PLoS Computational Biology, 11(3), e1004055. https://doi.org/10.1371/journal.pcbi.1004055
Garcia‐Marcos,, M., Kietrsunthorn,, P. S., Wang,, H., Ghosh,, P., & Farquhar,, M. G. (2011). G protein binding sites on Calnuc (Nucleobindin 1) and NUCB2 (Nucleobindin 2) define a new class of Gαi‐regulatory motifs. The Journal of Biological Chemistry, 286(32), 28138–28149. https://doi.org/10.1074/jbc.M110.204099
Getz,, M., Swanson,, L., Sahoo,, D., Ghosh,, P., & Rangamani,, P. (2019). A predictive computational model reveals that GIV/Girdin serves as a tunable valve for EGFR‐stimulated cyclic AMP signals. Molecular Biology of the Cell, 30(13), 1621–1633. https://doi.org/10.1091/mbc.E18-10-0630
Ghosh,, P. (2015). Heterotrimeric G proteins as emerging targets for network based therapy in cancer: End of a long futile campaign striking heads of a hydra. Aging, 7(7), 469–474. https://doi.org/10.18632/aging.100781
Ghosh,, P., Beas,, A. O., Bornheimer,, S. J., Garcia‐Marcos,, M., Forry,, E. P., Johannson,, C., … Farquhar,, M. G. (2010). A Gαi–GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Molecular Biology of the Cell, 21(13), 2338–2354. https://doi.org/10.1091/mbc.E10-01-0028
Ghosh,, P., & Garcia‐Marcos,, M. (2019). Do all roads Lead to Rome in G‐protein activation? Trends in Biochemical Sciences, 45, 182–184. https://doi.org/10.1016/j.tibs.2019.10.010
Ghosh,, P., Rangamani,, P., & Kufareva,, I. (2017). The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block. Cell Cycle, 16(7), 607–612. https://doi.org/10.1080/15384101.2017.1282584
Gooding,, A. J., & Schiemann,, W. P. (2016). Harnessing protein kinase a activation to induce mesenchymal‐epithelial programs to eliminate chemoresistant, tumor‐initiating breast cancer cells. Translational Cancer Research, 5(Suppl 2), S226–S232. https://doi.org/10.21037/tcr.2016.08.09
Gupta,, V., Bhandari,, D., Leyme,, A., Aznar,, N., Midde,, K. K., Lo,, I.‐C., … Ghosh,, P. (2016). GIV/Girdin activates Gαi and inhibits Gαs via the same motif. Proceedings of the National Academy of Sciences of the United States of America, 113(39), E5721–E5730. https://doi.org/10.1073/pnas.1609502113
Hartung,, A., Ordelheide,, A.‐M., Staiger,, H., Melzer,, M., Häring,, H.‐U., & Lammers,, R. (2013). The Akt substrate Girdin is a regulator of insulin signaling in myoblast cells. Biochimica et Biophysica Acta (BBA) ‐ Molecular Cell Research, 1833(12), 2803–2811. https://doi.org/10.1016/j.bbamcr.2013.07.012
Hayano,, S., Takefuji,, M., Maeda,, K., Noda,, T., Ichimiya,, H., Kobayashi,, K., … Murohara,, T. (2015). Akt‐dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 88, 55–63. https://doi.org/10.1016/j.yjmcc.2015.09.012
Hepp,, R., Tricoire,, L., Hu,, E., Gervasi,, N., Paupardin‐Tritsch,, D., Lambolez,, B., & Vincent,, P. (2007). Phosphodiesterase type 2 and the homeostasis of cyclic GMP in living thalamic neurons. Journal of Neurochemistry, 102(6), 1875–1886. https://doi.org/10.1111/j.1471-4159.2007.04657.x
Houglum,, K., Lee,, K. S., & Chojkier,, M. (1997). Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133. The Journal of Clinical Investigation, 99(6), 1322–1328. https://doi.org/10.1172/JCI119291
Houslay,, M. D., & Milligan,, G. (1997). Tailoring cAMP‐signalling responses through isoform multiplicity. Trends in Biochemical Sciences, 22(6), 217–224. https://doi.org/10.1016/S0968-0004(97)01050-5
Iadevaia,, S., Nakhleh,, L. K., Azencott,, R., & Ram,, P. T. (2014). Mapping network motif tunability and robustness in the design of synthetic signaling circuits. PLoS One, 9(3), e91743. https://doi.org/10.1371/journal.pone.0091743
Insel,, P. A., Murray,, F., Yokoyama,, U., Romano,, S., Yun,, H., Brown,, L., … Aroonsakool,, N. (2012). CAMP and Epac in the regulation of tissue fibrosis. British Journal of Pharmacology, 166(2), 447–456. https://doi.org/10.1111/j.1476-5381.2012.01847.x
Ito,, T., Komeima,, K., Yasuma,, T., Enomoto,, A., Asai,, N., Asai,, M., … Terasaki,, H. (2013). Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina. The American Journal of Pathology, 182(2), 586–596. https://doi.org/10.1016/j.ajpath.2012.10.012
Kalogriopoulos,, N. A., Rees,, S. D., Ngo,, T., Kopcho,, N. J., Ilatovskiy,, A. V., Sun,, N., … Kufareva,, I. (2019). Structural basis for GPCR‐independent activation of heterotrimeric Gi proteins. Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16394–16403. https://doi.org/10.1073/pnas.1906658116
Kawada,, N., Kuroki,, T., Kobayashi,, K., Inoue,, M., & Kaneda,, K. (1996). Inhibition of myofibroblastic transformation of cultured rat hepatic stellate cells by methylxanthines and dibutyryl cAMP. Digestive Diseases and Sciences, 41(5), 1022–1029. https://doi.org/10.1007/bf02091547
Kenakin,, T. (2004). Principles: Receptor theory in pharmacology. Trends in Pharmacological Sciences, 25(4), 186–192. https://doi.org/10.1016/j.tips.2004.02.012
Kholodenko,, B. N., Demin,, O. V., Moehren,, G., & Hoek,, J. B. (1999). Quantification of short term signaling by the epidermal growth factor receptor. Journal of Biological Chemistry, 274(42), 30169–30181. https://doi.org/10.1074/jbc.274.42.30169
Kida,, Y., Nyomba,, B. L., Bogardus,, C., & Mott,, D. M. (1991). Defective insulin response of cyclic adenosine monophosphate‐dependent protein kinase in insulin‐resistant humans. The Journal of Clinical Investigation, 87(2), 673–679. https://doi.org/10.1172/JCI115045
Kirsch,, D., Kemmler,, W., & Häring,, H. U. (1983). Cyclic AMP modulates insulin binding and induces post‐receptor insulin resistance of glucose transport in isolated rat adipocytes. Biochemical and Biophysical Research Communications, 115(1), 398–405. https://doi.org/10.1016/0006-291x(83)91017-3
Kirsch,, D. M., Bachmann,, W., & Häring,, H. U. (1984). Ciglitazone reverses cAMP‐induced post‐insulin receptor resistance in rat adipocytes in vitro. FEBS Letters, 176(1), 49–54. https://doi.org/10.1016/0014-5793(84)80909-6
Kirschner,, M., & Gerhart,, J. (1998). Evolvability. Proceedings of the National Academy of Sciences, 95(15), 8420–8427. https://doi.org/10.1073/pnas.95.15.8420
Kirsten,, L., Michael,, B., & Gerd,, H. (2006). Cyclic adenosine monophosphate in acute myocardial infarction with heart failure. Circulation, 114(5), 365–367. https://doi.org/10.1161/CIRCULATIONAHA.106.642132
Kitamura,, T., Kitamura,, Y., Kuroda,, S., Hino,, Y., Ando,, M., Kotani,, K., … Kasuga,, M. (1999). Insulin‐induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine‐threonine kinase Akt. Molecular and Cellular Biology, 19(9), 6286–6296. https://doi.org/10.1128/MCB.19.9.6286
Kitano,, H. (2004). Cancer as a robust system: Implications for anticancer therapy. Nature Reviews. Cancer, 4(3), 227–235. https://doi.org/10.1038/nrc1300
Kramer,, W., Thormann,, J., Kindler,, M., & Schlepper,, M. (1987). Effects of forskolin on left ventricular function in dilated cardiomyopathy. Arzneimittel‐Forschung, 37(3), 364–367.
Kreutner,, W., Chapman,, R. W., Gulbenkian,, A., & Tozzi,, S. (1985). Bronchodilator and antiallergy activity of forskolin. European Journal of Pharmacology, 111(1), 1–8. https://doi.org/10.1016/0014-2999(85)90106-2
Le‐Niculescu,, H., Niesman,, I., Fischer,, T., DeVries,, L., & Farquhar,, M. G. (2005). Identification and characterization of GIV, a novel Galpha i/s‐interacting protein found on COPI, endoplasmic reticulum‐Golgi transport vesicles. The Journal of Biological Chemistry, 280(23), 22012–22020. https://doi.org/10.1074/jbc.M501833200
Leyme,, A., Marivin,, A., & Garcia‐Marcos,, M. (2016). GIV/Girdin (Gα‐interacting, vesicle‐associated protein/Girdin) creates a positive feedback loop that potentiates outside‐in integrin signaling in cancer cells. The Journal of Biological Chemistry, 291(15), 8269–8282. https://doi.org/10.1074/jbc.M115.691550
Leyme,, A., Marivin,, A., Perez‐Gutierrez,, L., Nguyen,, L. T., & Garcia‐Marcos,, M. (2015). Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin. The Journal of Cell Biology, 210(7), 1165–1184. https://doi.org/10.1083/jcb.201506041
Lin,, C., Ear,, J., Midde,, K., Lopez‐Sanchez,, I., Aznar,, N., Garcia‐Marcos,, M., … Ghosh,, P. (2014). Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. Molecular Biology of the Cell, 25(22), 3654–3671. https://doi.org/10.1091/mbc.E14-05-0978
Lin,, C., Ear,, J., Pavlova,, Y., Mittal,, Y., Kufareva,, I., Ghassemian,, M., … Ghosh,, P. (2011). Tyrosine phosphorylation of the guanine nucleotide exchange factor GIV promotes activation of PI3K during cell migration. Science Signaling, 4(192), ra64. https://doi.org/10.1126/scisignal.2002049
Liu,, L., Jiang,, P., Cui,, D., Du,, J., He,, L., Yao,, J., & Liu,, D. (2015). Expression of Girdin in brain tissues of Alzheimer`s disease. Zhonghua Bing Li Xue Za Zhi = Chinese Journal of Pathology, 44(5), 301–304.
Lo Nigro,, C., Ricci,, V., Vivenza,, D., Granetto,, C., Fabozzi,, T., Miraglio,, E., & Merlano,, M. C. (2016). Prognostic and predictive biomarkers in metastatic colorectal cancer anti‐EGFR therapy. World Journal of Gastroenterology, 22(30), 6944–6954. https://doi.org/10.3748/wjg.v22.i30.6944
Lopez‐Sanchez,, I., Dunkel,, Y., Roh,, Y.‐S., Mittal,, Y., De Minicis,, S., Muranyi,, A., … Ghosh,, P. (2014). GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. Nature Communications, 5, 4451. https://doi.org/10.1038/ncomms5451
Lopez‐Sanchez,, I., Kalogriopoulos,, N., Lo,, I.‐C., Kabir,, F., Midde,, K. K., Wang,, H., & Ghosh,, P. (2015). Focal adhesions are foci for tyrosine‐based signal transduction via GIV/Girdin and G proteins. Molecular Biology of the Cell, 26(24), 4313–4324. https://doi.org/10.1091/mbc.E15-07-0496
Ma,, G. S., Aznar,, N., Kalogriopoulos,, N., Midde,, K. K., Lopez‐Sanchez,, I., Sato,, E., … Ghosh,, P. (2015). Therapeutic effects of cell‐permeant peptides that activate G proteins downstream of growth factors. Proceedings of the National Academy of Sciences of the United States of America, 112(20), E2602–E2610. https://doi.org/10.1073/pnas.1505543112
Ma,, G. S., Lopez‐Sanchez,, I., Aznar,, N., Kalogriopoulos,, N., Pedram,, S., Midde,, K., … Ghosh,, P. (2015). Activation of G proteins by GIV‐GEF is a pivot point for insulin resistance and sensitivity. Molecular Biology of the Cell, 26(23), 4209–4223. https://doi.org/10.1091/mbc.E15-08-0553
MacKenzie,, S. J., Baillie,, G. S., McPhee,, I., MacKenzie,, C., Seamons,, R., McSorley,, T., … Houslay,, M. D. (2002). Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A‐mediated phosphorylation of a single serine residue in upstream conserved region 1 (UCR1). British Journal of Pharmacology, 136(3), 421–433. https://doi.org/10.1038/sj.bjp.0704743
Makino,, H., Kanatsuka,, A., Suzuki,, T., Kuribayashi,, S., Hashimoto,, N., Yoshida,, S., & Nishimura,, M. (1985). Insulin resistance of fat cells from spontaneously diabetic KK mice: Analysis of insulin‐sensitive Phosphodiesterase. Diabetes, 34(9), 844–849. https://doi.org/10.2337/diab.34.9.844
Martínez,, M., Fernández,, E., Frank,, A., Guaza,, C., de la Fuente,, M., & Hernanz,, A. (1999). Increased cerebrospinal fluid cAMP levels in Alzheimer`s disease. Brain Research, 846(2), 265–267. https://doi.org/10.1016/s0006-8993(99)01981-2
McEwan,, D. G., Brunton,, V. G., Baillie,, G. S., Leslie,, N. R., Houslay,, M. D., & Frame,, M. C. (2007). Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4‐regulated compartment via effects on phosphoinositide 3‐kinase. Cancer Research, 67(11), 5248–5257. https://doi.org/10.1158/0008-5472.CAN-07-0097
Midde,, K., Sun,, N., Rohena,, C., Joosen,, L., Dhillon,, H., & Ghosh,, P. (2018). Single‐cell imaging of metastatic potential of cancer cells. IScience, 10, 53–65. https://doi.org/10.1016/j.isci.2018.11.022
Midde,, K. K., Aznar,, N., Kalogriopoulos,, N., & Ghosh,, P. (2016). Heterotrimeric G proteins: Breaking the rules of engagement, space and time. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 38(4), 379–393. https://doi.org/10.1002/bies.201500133
Midde,, K. K., Aznar,, N., Laederich,, M. B., Ma,, G. S., Kunkel,, M. T., Newton,, A. C., & Ghosh,, P. (2015). Multimodular biosensors reveal a novel platform for activation of G proteins by growth factor receptors. Proceedings of the National Academy of Sciences of the United States of America, 112(9), E937–E946. https://doi.org/10.1073/pnas.1420140112
Miyachi,, H., Takahashi,, M., & Komori,, K. (2015). A novel approach against vascular intimal hyperplasia through the suppression of Girdin. Annals of Vascular Diseases, 8(2), 69–73. https://doi.org/10.3400/avd.ra.14-00129
Murata,, K., Sudo,, T., Kameyama,, M., Fukuoka,, H., Mukai,, M., Doki,, Y., … Imaoka,, S. (2000). Cyclic AMP specific phosphodiesterase activity and colon cancer cell motility. Clinical %26 Experimental Metastasis, 18(7), 599–604. https://doi.org/10.1023/A:1011926116777
Murthy,, K. S., Zhou,, H., & Makhlouf,, G. M. (2002). PKA‐dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle. American Journal of Physiology. Cell Physiology, 282(3), C508–C517. https://doi.org/10.1152/ajpcell.00373.2001
Nagamatsu,, T., Nishiyama,, T., Goto,, I., Nagao,, T., & Suzuki,, Y. (2003). Adenosine 3′, 5′ cyclic monophosphate attenuates the production of fibronectin in the glomeruli of anti‐glomerular basement membrane antibody‐associated nephritic rats. British Journal of Pharmacology, 140(7), 1245–1251. https://doi.org/10.1038/sj.bjp.0705564
Newton,, A. C., Bootman,, M. D., & Scott,, J. D. (2016). Second messengers. Cold Spring Harbor Perspectives in Biology, 8(8), a005926. https://doi.org/10.1101/cshperspect.a005926
Oda,, K., Matsuoka,, Y., Funahashi,, A., & Kitano,, H. (2005). A comprehensive pathway map of epidermal growth factor receptor signaling. Molecular Systems Biology, 1, 2005.0010. https://doi.org/10.1038/msb4100014
Ou,, Y., Zheng,, X., Gao,, Y., Shu,, M., Leng,, T., Li,, Y., … Hu,, H. (2014). Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4‐dependent microtubule dynamics. Urologic Oncology, 32(1), 47.e21–47.e28. https://doi.org/10.1016/j.urolonc.2013.06.017
Pantziarka,, P., Sukhatme,, V., Crispino,, S., Bouche,, G., Meheus,, L., & Sukhatme,, V. P. (2018). Repurposing drugs in oncology (ReDO)—Selective PDE5 inhibitors as anti‐cancer agents. Ecancermedicalscience, 12, 824. https://doi.org/10.3332/ecancer.2018.824
Parag‐Sharma,, K., Leyme,, A., DiGiacomo,, V., Marivin,, A., Broselid,, S., & Garcia‐Marcos,, M. (2016). Membrane recruitment of the non‐receptor protein GIV/Girdin (Gα‐interacting, vesicle‐associated protein/Girdin) is sufficient for activating Heterotrimeric G protein signaling. Journal of Biological Chemistry, 291(53), 27098–27111. https://doi.org/10.1074/jbc.M116.764431
Perez,, D. R., Smagley,, Y., Garcia,, M., Carter,, M. B., Evangelisti,, A., Matlawska‐Wasowska,, K., … Chigaev,, A. (2016). Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia. Oncotarget, 7(23), 33960–33982. https://doi.org/10.18632/oncotarget.8986
Pierce,, K. L., Premont,, R. T., & Lefkowitz,, R. J. (2002). Seven‐transmembrane receptors. Nature Reviews Molecular Cell Biology, 3(9), 639–650. https://doi.org/10.1038/nrm908
Poppleton,, H., Sun,, H., Fulgham,, D., Bertics,, P., & Patel,, T. B. (1996). Activation of G by the epidermal growth factor receptor involves phosphorylation. Journal of Biological Chemistry, 271(12), 6947–6951. https://doi.org/10.1074/jbc.271.12.6947
Raker,, V. K., Becker,, C., & Steinbrink,, K. (2016). The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Frontiers in Immunology, 7, 123. https://doi.org/10.3389/fimmu.2016.00123
Ramirez,, C. E., Nian,, H., Yu,, C., Gamboa,, J. L., Luther,, J. M., Brown,, N. J., & Shibao,, C. A. (2015). Treatment with sildenafil improves insulin sensitivity in Prediabetes: A randomized, controlled trial. The Journal of Clinical Endocrinology and Metabolism, 100(12), 4533–4540. https://doi.org/10.1210/jc.2015-3415
Sassone‐Corsi,, P. (2012). The cyclic AMP pathway. Cold Spring Harbor Perspectives in Biology, 4(12), a011148. https://doi.org/10.1101/cshperspect.a011148
Savai,, R., Pullamsetti,, S. S., Banat,, G.‐A., Weissmann,, N., Ghofrani,, H. A., Grimminger,, F., & Schermuly,, R. T. (2010). Targeting cancer with phosphodiesterase inhibitors. Expert Opinion on Investigational Drugs, 19(1), 117–131. https://doi.org/10.1517/13543780903485642
Serezani,, C. H., Ballinger,, M. N., Aronoff,, D. M., & Peters‐Golden,, M. (2008). Cyclic AMP. American Journal of Respiratory Cell and Molecular Biology, 39(2), 127–132. https://doi.org/10.1165/rcmb.2008-0091TR
Sette,, C., & Conti,, M. (1996). Phosphorylation and activation of a cAMP‐specific phosphodiesterase by the cAMP‐dependent protein kinase. Involvement of serine 54 in the enzyme activation. The Journal of Biological Chemistry, 271(28), 16526–16534.
Shimizu,, E., Kobayashi,, Y., Oki,, Y., Kawasaki,, T., Yoshimi,, T., & Nakamura,, H. (1999). OPC‐13013, a cyclic nucleotide phosphodiesterase type III, inhibitor, inhibits cell proliferation and transdifferentiation of cultured rat hepatic stellate cells. Life Sciences, 64(23), 2081–2088. https://doi.org/10.1016/s0024-3205(99)00157-5
Sigismund,, S., Avanzato,, D., & Lanzetti,, L. (2018). Emerging functions of the EGFR in cancer. Molecular Oncology, 12(1), 3–20. https://doi.org/10.1002/1878-0261.12155
Silva,, A. J., Kogan,, J. H., Frankland,, P. W., & Kida,, S. (1998). CREB and memory. Annual Review of Neuroscience, 21, 127–148. https://doi.org/10.1146/annurev.neuro.21.1.127
Simpson,, F., Martin,, S., Evans,, T. M., Kerr,, M., James,, D. E., Parton,, R. G., … Wicking,, C. (2005). A novel hook‐related protein family and the characterization of hook‐related protein 1. Traffic, 6(6), 442–458. https://doi.org/10.1111/j.1600-0854.2005.00289.x
Tagliaferri,, P., Katsaros,, D., Clair,, T., Ally,, S., Tortora,, G., Neckers,, L., … Cho‐Chung,, Y. S. (1988). Synergistic inhibition of growth of breast and colon human cancer cell lines by site‐selective cyclic AMP analogues. Cancer Research, 48(6), 1642–1650.
Tang,, Y., Osawa,, H., Onuma,, H., Nishimiya,, T., Ochi,, M., & Makino,, H. (1999). Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice. Diabetes, 48(9), 1830–1835. https://doi.org/10.2337/diabetes.48.9.1830
Tanti,, J. F., Grémeaux,, T., Rochet,, N., Obberghen,, E. V., & Marchand‐Brustel,, Y. L. (1987). Effect of cyclic AMP‐dependent protein kinase on insulin receptor tyrosine kinase activity. Biochemical Journal, 245(1), 19–26. https://doi.org/10.1042/bj2450019
Thomas,, R., & Weihua,, Z. (2019). Rethink of EGFR in cancer with its kinase independent function on board. Frontiers in Oncology, 9, 800. https://doi.org/10.3389/fonc.2019.00800
Tremblay,, J., Lachance,, B., & Hamet,, P. (1985). Activation of cyclic GMP‐binding and cyclic AMP‐specific phosphodiesterases of rat platelets by a mechanism involving cyclic AMP‐dependent phosphorylation. Journal of Cyclic Nucleotide and Protein Phosphorylation Research, 10(4), 397–411.
Van Daalen,, E., Kemner,, C., Verbeek,, N. E., van der Zwaag,, B., Dijkhuizen,, T., Rump,, P., … Poot,, M. (2011). Social responsiveness scale‐aided analysis of the clinical impact of copy number variations in autism. Neurogenetics, 12(4), 315–323. https://doi.org/10.1007/s10048-011-0297-2
Vitale,, G., Dicitore,, A., Mari,, D., & Cavagnini,, F. (2009). A new therapeutic strategy against cancer: CAMP elevating drugs and leptin. Cancer Biology %26 Therapy, 8(12), 1191–1193. https://doi.org/10.4161/cbt.8.12.8937
Wachtel,, H., & Löschmann,, P. A. (1986). Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: Interactions with rolipram. Psychopharmacology, 90(4), 430–435. https://doi.org/10.1007/bf00174056
Wang,, H., Misaki,, T., Taupin,, V., Eguchi,, A., Ghosh,, P., & Farquhar,, M. G. (2015). GIV/girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin. Journal of the American Society of Nephrology, 26(2), 314–327. https://doi.org/10.1681/ASN.2013090985
Wang,, W., Li,, Y., Zhu,, J. Y., Fang,, D., Ding,, H.‐F., Dong,, Z., … Huang,, S. (2016). Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition. Oncotarget, 7(52), 87232–87245. https://doi.org/10.18632/oncotarget.13601
Waugh,, M. G. (2012). Phosphatidylinositol 4‐kinases, phosphatidylinositol 4‐phosphate and cancer. Cancer Letters, 325(2), 125–131. https://doi.org/10.1016/j.canlet.2012.06.009
Weng,, L., Enomoto,, A., Miyoshi,, H., Takahashi,, K., Asai,, N., Morone,, N., … Takahashi,, M. (2014). Regulation of cargo‐selective endocytosis by dynamin 2 GTPase‐activating protein girdin. The EMBO Journal, 33(18), 2098–2112. https://doi.org/10.15252/embj.201488289
Westphal,, M., Maire,, C. L., & Lamszus,, K. (2017). EGFR as a target for Glioblastoma treatment: An unfulfilled promise. CNS Drugs, 31(9), 723–735. https://doi.org/10.1007/s40263-017-0456-6
Yang,, P.‐C., Boras,, B. W., Jeng,, M.‐T., Docken,, S. S., Lewis,, T. J., McCulloch,, A. D., … Clancy,, C. E. (2016). A computational modeling and simulation approach to investigate mechanisms of subcellular cAMP compartmentation. PLoS Computational Biology, 12(7), e1005005. https://doi.org/10.1371/journal.pcbi.1005005
Yu,, L., Sun,, Y., Li,, J., Wang,, Y., Zhu,, Y., Shi,, Y., … Cao,, P. (2017). Silencing the Girdin gene enhances radio‐sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism. Journal of Experimental %26 Clinical Cancer Research, 36(1), 110. https://doi.org/10.1186/s13046-017-0580-7
Zhang,, Y.‐J., Li,, A.‐J., Han,, Y., Yin,, L., & Lin,, M.‐B. (2014). Inhibition of Girdin enhances chemosensitivity of colorectal cancer cells to oxaliplatin. World Journal of Gastroenterology, 20(25), 8229–8236. https://doi.org/10.3748/wjg.v20.i25.8229
Zimmerman,, N. P., Roy,, I., Hauser,, A. D., Wilson,, J. M., Williams,, C. L., & Dwinell,, M. B. (2015). Cyclic AMP regulates the migration and invasion potential of human pancreatic cancer cells. Molecular Carcinogenesis, 54(3), 203–215. https://doi.org/10.1002/mc.22091

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

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

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox