What is the role of cyclic AMP in signal transduction

1. Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine, California 92697

1. Correspondence: psc{at}uci.edu

Cyclic adenosine 3′,5′-monophosphate (cAMP) was the first second messenger to be identified and plays fundamental roles in cellular responses to many hormones and neurotransmitters (Sutherland and Rall 1958). The intracellular levels of cAMP are regulated by the balance between the activities of two enzymes (see Fig. 1): adenylyl cyclase (AC) and cyclic nucleotide phosphodiesterase (PDE). Different isoforms of these enzymes are encoded by a large number of genes, which differ in their expression patterns and mechanisms of regulation, generating cell-type and stimulus-specific responses (McKnight 1991).

Most ACs (soluble bicarbonate-regulated ACs are the exception) are activated downstream from G-protein-coupled receptors (GPCRs) such as the β adrenoceptor by interactions with the α subunit of the Gs protein (αs). αs is released from heterotrimeric αβγ G-protein complexes following binding of agonist ligands to GPCRs (e.g., epinephrine in the case of β adrenoceptors) and binds to and activates AC. The βγ subunits can also stimulate some AC isoforms. cAMP generated as a consequence of AC activation can activate several effectors, the most well studied of which is cAMP-dependent protein kinase (PKA) (Pierce et al. 2002).

Alternatively, AC activity can be inhibited by ligands that stimulate GPCRs coupled to Gi and/or cAMP can be degraded by PDEs. Indeed both ACs and PDEs are regulated positively and negatively by numerous other signaling pathways (see Fig. 2), such as calcium signaling (through calmodulin [CaM], CamKII, CamKIV, and calcineurin [also know as PP2B]), subunits of other G proteins (e.g., αi, αo, and αq proteins, and the βγ subunits in some cases), inositol lipids (by PKC), and receptor tyrosine kinases (through the ERK MAP kinase and PKB) (Yoshimasa et al. 1987; Bruce et al. 2003; Goraya and Cooper 2005). Crosstalk with other pathways provides further modulation of the signal strength and cell-type specificity, and feedforward signaling by PKA itself stimulates PDE4.

There are three main effectors of cAMP: PKA, the guanine-nucleotide-exchange factor (GEF) EPAC and cyclic-nucleotide-gated ion channels. Protein kinase (PKA), the best-understood target, is a symmetrical complex of two regulatory (R) subunits and two catalytic (C) subunits (there are several isoforms of both subunits). It is activated by the binding of cAMP to two sites on each of the R subunits, which causes their dissociation from the C subunits (Taylor et al. 1992). The catalytic activity of the C subunit is decreased by a protein kinase inhibitor (PKI), which can also act as a chaperone and promote nuclear export of the C subunit, thereby decreasing nuclear functions of PKA. PKA-anchoring proteins (AKAPs) provide specificity in cAMP signal transduction by placing PKA close to specific effectors and substrates. They can also target it to particular subcellular locations and anchor it to ACs (for immediate local activation of PKA) or PDEs (to create local negative feedback loops for signal termination) (Wong and Scott 2004).

A large number of cytosolic and nuclear proteins have been identified as substrates for PKA (Tasken et al. 1997). PKA phosphorylates numerous metabolic enzymes, including glycogen synthase and phosphorylase kinase, which inhibits glycogen synthesis and promotes glycogen breakdown, respectively, and acetyl CoA carboxylase, which inhibits lipid synthesis. PKA also regulates other signaling pathways. For example, it phosphorylates and thereby inactivates phospholipase C (PLC) β2. In contrast, it activates MAP kinases; in this case, PKA promotes phosphorylation and dissociation of an inhibitory tyrosine phosphatase (PTP). PKA also decreases the activities of Raf and Rho and modulates ion channel permeability. In addition, it regulates the expression and activity of various ACs and PDEs.

Regulation of transcription by PKA is mainly achieved by direct phosphorylation of the transcription factors cAMP-response element-binding protein (CREB), cAMP-responsive modulator (CREM), and ATF1. Phosphorylation is a crucial event because it allows these proteins to interact with the transcriptional coactivators CREB-binding protein (CBP) and p300 when bound to cAMP-response elements (CREs) in target genes (Mayr and Montminy 2001). The CREM gene also encodes the powerful repressor ICER, which negatively feeds back on cAMP-induced transcription (Sassone-Corsi 1995). Note, however, that the picture is more complex, because CREB, CREM, and ATF1 can all be phosphorylated by many different kinases, and PKA can also influence the activity of other transcription factors, including some nuclear receptors.

In addition to the negative regulation by signals that inhibit AC or stimulate PDE activity, the action of PKA is counterbalanced by specific protein phosphatases, including PP1 and PP2A. PKA in turn can negatively regulate phosphatase activity by phosphorylating and activating specific PP1 inhibitors, such as I1 and DARPP32. PKA-promoted phosphorylation can also increase the activity of PP2A as part of a negative feedback mechanism.

Another important effector for cAMP is EPAC, a GEF that promotes activation of certain small GTPases (e.g., Rap1). A major function of Rap1 is to increase cell adhesion via integrin receptors (how this occurs is unclear) (Bos 2003).

Finally, cAMP can bind to and modulate the function of a family of cyclic-nucleotide-gated ion channels. These are relatively nonselective cation channels that conduct calcium. Calcium stimulates CaM and CaM-dependent kinases and, in turn, modulates cAMP production by regulating the activity of ACs and PDEs (Zaccolo and Pozzan 2003). The channels are also permeable to sodium and potassium, which can alter the membrane potential in electrically active cells.

Figure 2 adapted from Fimia and Sassone-Corsi (2001).

Footnotes

• Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner

• Additional Perspectives on Signal Transduction available at www.cshperspectives.org

REFERENCES

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1. John W.B. Hershey1,
2. Nahum Sonenberg2 and
3. Michael B. Mathews3

1. 1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California 95616
2. 2Department of Biochemistry and Goodman Cancer Research Center, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
3. 3Department of Biochemistry and Molecular Biology, UMDNJ—New Jersey Medical School, Newark, New Jersey 07103-2714

1. Correspondence: jwhershey{at}ucdavis.edu; nahum.sonenberg{at}mcgill.ca; mathews{at}umdnj.edu

Translational control plays an essential role in the regulation of gene expression. It is especially important in defining the proteome, maintaining homeostasis, and controlling cell proliferation, growth, and development. Numerous disease states result from aberrant regulation of protein synthesis, so understanding the molecular basis and mechanisms of translational control is critical. Here we outline the pathway of protein synthesis, with special emphasis on the initiation phase, and identify areas needing further clarification. Features of translational control are described together with numerous specific examples, and we discuss prospects for future conceptual advances.

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1. Protein Synthesis and Translational Control

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1. DNA Repair, Mutagenesis, and Other Responses to DNA Damage

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1. The Endoplasmic Reticulum

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1. Morgan Sheng1,
2. Bernardo L. Sabatini2 and
3. Thomas C. Südhof3

1. 1Department of Neuroscience, Genentech Inc., South San Francisco, California 94080
2. 2Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
3. 3Howard Hughes Medical Institute, Department of Cellular and Molecular Physiology, Stanford University School of Medicine, Stanford, California 94305

1. Correspondence: sheng.morgan{at}gene.com

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein (“plaques”) and by insoluble filaments composed of hyperphosphorylated tau protein (“tangles”). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.

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1. College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom

1. Correspondence: d.g.hardie{at}dundee.ac.uk

All living organisms maintain a high ATP:ADP ratio to drive energy-requiring processes. They therefore need mechanisms to maintain energy balance at the cellular level. In addition, multicellular eukaryotes have assigned the task of storing energy to specialized cells such as adipocytes, and therefore also need a means of intercellular communication to signal the needs of individual tissues and to maintain overall energy balance at the whole body level. Such signaling allows animals to survive periods of fasting or starvation when food is not available and is mainly achieved by hormonal and nervous communication. Insulin, adipokines, epinephrine, and other agonists thus stimulate pathways that regulate the activities of key enzymes involved in control of metabolism to integrate organismal carbohydrate and lipid metabolism. Overnutrition can dysregulate these pathways and have damaging consequences, causing insulin resistance and type 2 diabetes.

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1. Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, California 94305-5428

1. Correspondence: rnusse{at}stanford.edu

Members of the Wnt family are secreted ligands that regulate numerous developmental pathways (Cadigan and Peifer 2009; Van Amerongen and Nusse 2009; and see Neel and Muthuswarmy 2012; Perrimon and Shilo 2012). Wnt binds to members of the Frizzled family, activating a canonical signaling pathway that targets members of the LEF/TCF transcription factor family (Fig. 1). These control gene expression programs that regulate cell fate and morphogenesis (Van Amerongen and Nusse 2009). Wnt also activates so-called non-canonical pathways (Fig. 2), which regulate planar cell polarity by stimulating cytoskeletal reorganization and can also lead to calcium mobilization (Veeman et al. 2003).

The canonical Wnt signaling pathway is regulated at many levels, including by extensive negative control steps. In cells not exposed to Wnt signals, the major signaling components including the receptors and the β-catenin protein are kept in an off state (Fig. 1, left). Active Wnt signaling rearranges these complexes (Fig. 1, right). In the inactive state, β-catenin levels are kept low through interactions with the protein kinases GSK-3b and CK1, the adenomatous polyposis coli tumor suppressor protein (APC), and the scaffolding protein axin. β-Catenin is degraded, after phosphorylation by GSK-3 and CK1 through the ubiquitin pathway, which involves interactions with β-TrCP. β-Catenin is also regulated by adhesion complexes containing cadherins and α-catenin. At the level of receptors, the negative regulator DKK can bind to the LRP receptor and inhibit Wnt signaling.

During signaling (right), Wnt proteins interact with Frizzled receptors; the transmembrane protein LRP is also required for Wnt signaling. When Wnt proteins bind, the receptors presumably rearrange, leading to the activation of β-catenin. The cytoplasmic tail of LRP binds to axin in a Wnt- and phosphorylation-dependent manner. Phosphorylation of the tail of LRP is regulated by CK1, and Dishevelled (Dvl) and Frizzled also have roles in this process. In a current model, Wnt signaling initially leads to formation of a complex involving Dvl, axin, and GSK3. The DIX domain in axin is similar to the NH2 terminus in Dvl and promotes interactions between Dvl and axin. As a consequence, GSK does not phosphorylate β-catenin anymore, releasing it from the axin complex and allowing it to accumulate. The stabilized β-catenin then enters the nucleus to interact with TCF/LEF transcription factors. Note that GSK3 also participates in other pathways, such as the mTor and Akt pathway (see Hemmings 2012; Laplante and Sabatini 2012).

In the nucleus, in the absence of the Wnt signal, TCF/LEF acts as a repressor of Wnt target genes, in a complex with Groucho. β-Catenin can convert TCF/LEF into a transcriptional activator of the same genes that are repressed by TCF/LEF alone. Three other key players in this complex are BCL9, Pygopos, and CBP. There are many target genes for the canonical Wnt pathway. Most of these genes are cell type specific, with the possible exception of axin 2, which acts as a negative feedback regulator (Grigoryan 2008).

In non-canonical Wnt signaling, Wnt stimulates the planar cell polarity pathway by activating the small GTPases Rho and Rac. These induce cytoskeletal rearrangements that lead to the development of lateral asymmetry in epithelial sheets and other structures. Wnt can also provoke release of calcium from intracellular stores, probably via heterotrimeric G-proteins. A less-well-understood mechanism involves activation of the Ror and Ryk tyrosine kinase receptors, which control the activities of the JNK and Src kinases, respectively (van Amerongen et al. 2008).

Footnotes

• Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy W. Thorner

• Additional Perspectives on Signal Transduction available at www.cshperspectives.org

*Reference is also in this collection.

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1. Daniel N. Wilson1,2 and
2. Jamie H. Doudna Cate3,4

1. 1Center for Integrated Protein Science Munich (CiPSM), 81377 Munich, Germany
2. 2Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
3. 3Departments of Molecular and Cell Biology and Chemistry, University of California at Berkeley, Berkeley, California 94720
4. 4Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

1. Correspondence: wilson{at}lmb.uni-muenchen.de and jcate{at}lbl.gov

Structures of the bacterial ribosome have provided a framework for understanding universal mechanisms of protein synthesis. However, the eukaryotic ribosome is much larger than it is in bacteria, and its activity is fundamentally different in many key ways. Recent cryo-electron microscopy reconstructions and X-ray crystal structures of eukaryotic ribosomes and ribosomal subunits now provide an unprecedented opportunity to explore mechanisms of eukaryotic translation and its regulation in atomic detail. This review describes the X-ray crystal structures of the Tetrahymena thermophila 40S and 60S subunits and the Saccharomyces cerevisiae 80S ribosome, as well as cryo-electron microscopy reconstructions of translating yeast and plant 80S ribosomes. Mechanistic questions about translation in eukaryotes that will require additional structural insights to be resolved are also presented.

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1. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

1. Correspondence: cmghajar{at}lbl.gov

That cancer is development gone awry is not a new concept. Most of the “hallmarks” ascribed to cancer—proliferation, invasion and induction of blood vessel growth—also occur during organogenesis and development. Therefore, tumors are not necessarily learning new tricks during their development, but how about when they metastasize? In colonizing a new organ, often with some degree of specificity, tumor cells may simply be copying a program that is executed during development by hematopoietic stem cells (HSCs)—the stem cells that ultimately generate all of the cells in our blood and maintain its homeostasis. One family of cells generated by HSCs—leukocytes—is the focus of the work by Coussens and Pollard (2012). These two scientists have woven together several studies that revolutionized the way we think of immune cells. As pointed out by the investigators (whose respective laboratories are responsible for much of the seminal work on this subject), immune cells also have a variety of trophic functions, and it is these functions that are used rationally during development, and recklessly during tumor growth.

This leads us back to metastasis. There is so much to learn about why a tumor travels from one organ to another, how it does so, and the manner by which it adapts to and ultimately flourishes (or fails) in a foreign microenvironment. And as stated above, immune cell precursors, HSCs, do the same. In the mouse, HSCs have originated in one tissue (the dorsal aorta), traveled to another (the placenta) via the circulation, and matured somewhere else (the liver)—all before birth. Finally, HSCs make their way to the bone marrow, where they reside postnatally. Specialized niches in the bone marrow are thought to mediate HSC dormancy as a means to preserve the “stemness” of this population, and there are mechanisms in place that allow these cells to rapidly exit these environs and proliferate in response to injury. Therefore, it should not come as a surprise that a common site where micrometastases are found is the bone marrow for many cancers (including that of the breast).

Uncovering whether the same niches that control HSC expansion in the bone marrow are also responsible for maintaining quiescence of tumor cell populations is an exciting prospect, as is deciphering the precise components of these niches. Such work could explain the seemingly incongruous observation that despite an absence of clinically detectable disease, circulating tumor cells are present in the blood of post-treatment cancer patients sometimes even decades later! Perhaps the niches that regulate prolonged dormancy of tumors are dynamic and inhibit tumor proliferation while allowing them to mobilize periodically, much like for HSCs. It also stands to reason that loss of the same controls that prevent HSC expansion until systemic damage occurs could awaken dormant tumors.

Shiozawa et al. (2011) have demonstrated that prostate cancer cells do in fact compete with HSCs for niches within the bone marrow, and that tumor cells are mobilized from HSC niches by similar mechanisms as for HSCs. Whether this is the case for other cancers and whether these similarities can be exploited therapeutically remain to be seen.

So what more is there to be learned about immune cells? By furthering our understanding of how solid cancers mimic and hijack components of our immune system, we may not “cure” cancer, but we very well may uncover a means to suppress some cancers into a state of permanent dormancy.

Footnotes

• Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey M. Rosen

• Additional Perspectives on The Mammary Gland as an Experimental Model available at www.cshperspectives.org

*Reference is also in this collection.

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1. Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

1. Correspondence: MALabarge{at}lbl.gov

Petersen and Polyak (2011) elegantly explain the developmental hierarchy of the human mammary gland as it is currently understood. It is amazing that the small pool of stem cells can be cyclically called on to give rise to the progenitors and more differentiated myoepithelial and luminal epithelial cells that are needed for expansion during monthly estrous cycles and in preparation for lactation. How do the stem cells respond so perfectly and repetitively throughout a woman’s childbearing years? Do stem cells harbor internal circadian clocks that work in time with similar clocks in the endocrine system and ovaries? Or are mammary stem cells able to respond to shifting physiological needs of the organism because their functions are controlled by their microenvironment, which changes with the ebb and flow of the physiological tide? That estrous cycles can vary according to life’s circumstances (e.g., changes in nutrition, exercise, or stress) and because lengths of pregnancies and lactation periods differ for each pregnancy, it seems likely that mammary stem cells are governed by an external control mechanism that interacts with systemic changes in physiology.

That stem cells and all of their progeny share identical genomes, and that stem cells reside inside niche microenvironments that are completely unique as compared to those of the surrounding tissue, suggests that microenvironments exert a tremendous influence over stem cell behavior. Even mathematical models of hematopoiesis suggested that stem cell-extrinsic regulation was the best way to explain why stem cells responded to a wide variety of physiological needs (Loeffler and Roeder 2002; Roeder and Lorenz 2006). Experimentally, microenvironmental control of mammary progenitors, hematopoietic stem cells, embryonic stem cells, and neural progenitors has been shown by use of functional assays on arrayed combinatorial microenvironments (Flaim et al. 2005; Soen et al. 2006; LaBarge et al. 2009; Lutolf et al. 2009). And perhaps the grandest demonstration of the power of the microenvironment over stem cell function was shown repeatedly when adult stem cells from one tissue were shown to give rise to other tissues after they were placed in tissue-specific microenvironments different from their native ones (Blau et al. 2001; Boulanger et al. 2007; Booth et al. 2008). An important likelihood that arises from those experiments is that the phenotype of a stem cell is probably affected by its microenvironment (LaBarge et al. 2007). To completely understand the identity and control of mammary stem cells, we must meticulously define the microenvironment(s) they inhabit.

As Petersen and Polyak point out, the methodology used to describe the stem cell hierarchy in adult hematopoietic systems has guided many subsequent studies aimed at identifying hierarchies in epithelial tissues. Accordingly, tissues are dissociated into suspensions of single cells, fractionated with a cell sorting technology, and the fractions are assayed for stem cell activity in a number of culture assays and in vivo when possible. Demonstration that a single cell can give rise to the tissue in question is often referred to as the “gold standard” experiment, and it is an unfortunate burden of proof held over from the hematopoietic field. Blood is an interesting tissue in that centers for hematopoiesis shift throughout development among locations that are anatomically close to the circulation, and it is thought that in adults, blood is produced from niches in marrow and vasculature (Sacchetti et al. 2007; Hooper et al. 2009; Butler et al. 2010). Thus, it makes sense that a single hematopoietic stem cell should regenerate the blood as nothing more is being asked of it than to do exactly what it was meant to, and to do it in the perfect microenvironment. Moreover, in the hematopoiesis model, where the microenvironment was essentially perfect, it stands to reason that one would only observe different activities according to the fraction from which single cells were derived. These facts may help explain why it has taken so long for acceptance of the idea that microenvironments can control stem cell activity. By comparison, adult mammary epithelial stem cells are distinct from the neonatal stem cells that made the initial mammary rudiment, and the adult stem cells evolved within an intricate epithelial architecture that was within a tissue stroma. That a single mouse mammary stem cell could give rise to an outgrowth was shown to occur at very low frequency (Shackleton et al. 2006; Stingl et al. 2006), and it has yet to be shown that a single normal human mammary stem cell can generate an outgrowth in a murine fat pad. Given the biological differences between blood and mammary epithelium, it is no surprise that the identity of human mammary stem cells and the mechanisms that govern them are still hotly debated.

Footnotes

• Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey M. Rosen

• Additional Perspectives on The Mammary Gland as an Experimental Model available at www.cshperspectives.org

*Reference is also in this collection.

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