Novel insights into G protein and G protein-coupled receptor signaling in cancer

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<ul><li><p>d </p><p>d</p><p>Available online at www.sciencedirect.com</p><p>ctof highly evolutionarily conserved a-arrestins has recentlyreceived attention due their implicated roles in GPCRtrafficking and degradation [3]. Most GPCRs will activateone or multiple Ga proteins, which can be subdivided intofour major families: Gai, Ga12, Gas, and Gaq, with eachfamily activating distinct signaling pathways [4]. GPCRscan also trigger G protein-independent mechanisms, in-cluding signaling through b-arrestins and interactions withPDZ containing proteins and other GPCR-regulators/scaffolding proteins [5]. GPCRs act more as molecular</p><p>messenger generating systems with the regulation ofproteinprotein interaction based networks. Some ofthese signaling circuits may act in cell type specificmanners to initiate or sustain cancer cell growth andthe metastatic spread of primary tumor lesions.</p><p>Second messenger generating systems</p><p>GPCR stimulation triggers the activation of heterotri-meric G proteins as GTP replaces GDP on the Ga</p><p>Current Opinion in Cell Biology 2014, 27:126135 www.sciencedirect.comNovel insights into G protein ansignaling in cancerMorgan OHayre, Maria S Degese an</p><p>G protein-coupled receptors (GPCRs) play a central role in</p><p>signal transmission, thereby controlling many facets of cellular</p><p>function. Overwhelming evidence now implicates GPCRs, G</p><p>proteins and their downstream signaling targets in cancer</p><p>initiation and progression, where they can influence aberrant</p><p>cell growth and survival, largely through activation of AKT/</p><p>mTOR, MAPKs, and Hippo signaling pathways. GPCRs also</p><p>play critical roles in the invasion and metastasis of cancer cells</p><p>via activation of Rho GTPases and cytoskeletal changes, and</p><p>angiogenesis to supply the tumor with nutrients and provide</p><p>routes for metastasis. Lastly, GPCRs contribute to the</p><p>establishment and maintenance of a permissive tumor</p><p>microenvironment. Understanding GPCR involvement in</p><p>cancer malignancy may help identify novel therapeutic</p><p>opportunities for cancer prevention and treatment.</p><p>Addresses</p><p>Oral and Pharyngeal Cancer Branch, Dental and Craniofacial Research,</p><p>National Institutes of Health, Bethesda, MD 20892, USA</p><p>Corresponding author: Gutkind, J Silvio (sg39v@nih.gov)</p><p>Current Opinion in Cell Biology 2014, 27:126135</p><p>This review comes from a themed issue on Cell regulation</p><p>Edited by Jeffrey L Benovic and Mark von Zastrow</p><p>Available online XXX</p><p>0955-0674/$ see front matter, Published by Elsevier Ltd.</p><p>http://dx.doi.org/10.1016/j.ceb.2014.01.005</p><p>IntroductionAgonist binding to G protein coupled receptors (GPCRs)results in rapid conformational changes that lead to theactivation of heterotrimeric G proteins, comprised of Ga, band g subunits, and the recruitment of proteins responsiblefor receptor internalization and desensitization, includingarrestins and GPCR kinases (GRKs) [1,2]. A novel family</p><p>ScienceDireG protein-coupled receptor</p><p> J Silvio Gutkind</p><p>rheostats rather than on-off switches, so the engagementof different G proteins and strength/duration of signalingmay not only differ between GPCRs, but also for a givenGPCR, depending on the ligand and cellular environment.</p><p>Early indications that GPCRs could function as oncogenesinclude characterization of the transforming capacity of themas proto-oncogene and other GPCRs in the presence ofexcess ligand availability, the identification of activatingoncogenic mutations in thyroid stimulating hormone re-ceptor (TSHR), and the association of virally encodedGPCRs with tumorigenesis [4]. Since then, many GPCRswere shown to be overexpressed in a variety of cancer typesand linked to tumor-cell growth when activated by circu-lating or locally produced ligands. Yet, despite the associ-ation of GPCRs with cancer progression and the fact thatGPCRs represent one of the most druggable classes ofmolecules, representing approximately 25% of all thera-peutics on the market, there are relatively few cancertreatments targeting GPCRs [6]. By better understandingthe molecular mechanisms underlying GPCR function incancer, we can identify the best therapeutic targets forcancer prevention and treatment.</p><p>GPCRs signaling in normal and cancer cellproliferation and survivalCell growth promotion has been traditionally associatedwith the activation of tyrosine kinase growth factor recep-tors (RTKs) [7]. The discovery and use of bacterial toxinsinhibiting G protein ai subunits [8] established thatmultiple mitogens transduce proliferative signals throughGPCRs, including thrombin and lysophosphatidic acid(LPA) [9,10,11]. Subsequent studies revealed thatmany mitogens act on GPCRs linked to the Gq andG12 G protein families, including many peptide hor-mones, bioactive lipid mediators, and neurotransmitters[4,12], supporting the involvement of GPCRs in cellproliferation in a variety of cell types [4,13,14]. Themolecular mechanisms underlying cell growth promotionby GPCRs is still an active area on investigation, as itinvolves the coordinated activation of traditional second</p></li><li><p>G protein, G protein-coupled receptor signaling in cancer OHayre, Degese and Gutkind 127</p><p>TRI</p><p>linsinnFigure 1</p><p>LPA</p><p>GTP</p><p>q/11</p><p>-arrestinGTP</p><p>i</p><p>Adenylylcyclase LARG</p><p>PRG p63</p><p>EndotheBombe</p><p>GastriGRP5-HT</p><p>GTP</p><p>12/13</p><p>S1PThrombinsubunit, promoting its dissociation from Gbg subunits.Both a-GTP bound and Gbg subunit complexes thenstimulate multiple downstream signaling cascades [2,4],including the rapid generation of multiple second mes-sengers. For example, Gas stimulates adenylyl cyclases,increasing the cytosolic levels of cAMP, while Gai inhi-bits adenylyl cyclases and hence decreases cAMP levels[15]. Members of the Gaq family activate phospholipase-Cb, which cleaves PIP2 into diacylglycerol (DAG) andinositol 1,4,5-trisphosphate (IP3); the latter causes anincrease in cytosolic calcium [16]. The targets of thesediffusible second messengers include ion channels,calcium-sensitive enzymes, and kinases such as cAMP-dependent kinase (PKA), protein kinase C (PKC),cGMP-dependent kinase (PKG), and calcium-calmodu-lin regulated kinases (CAMKs), which are stimulated by</p><p>PI3KRas GEFRac GEF</p><p>Rac</p><p>PAK</p><p>Nuclearevents</p><p>JNK</p><p>SRC</p><p>Ras</p><p>ERK</p><p>AKT</p><p>mTOR</p><p>Nuclearevents</p><p>Proteinsynthesis</p><p>Survival</p><p>p115</p><p>Rho</p><p>ROCK</p><p>Rac</p><p>JNK p38</p><p>Actinremodeling</p><p>Nuclear evenActin</p><p>remodeling</p><p>Activation of growth and survival pathways by GPCRs. Stimulation of GPCRs</p><p>messenger generating systems, guanine nucleotide exchange factors (GEFs</p><p>downstream cytosolic and nuclear targets. This signaling network contribute</p><p>aberrant activation of GPCRs/G proteins and their downstream targets can </p><p>mitogens acting on GPCRs stimulate Gaq/11, while others activate Ga12/13 a</p><p>multiple pathways regulated by Gbg subunits. In turn, these signaling routes</p><p>genes by the prolonged stimulation of transcription factors including c-FOS a</p><p>parallel, activation of PI3K and AKT can induce cell proliferation by regulating</p><p>apoptotic proteins. AKT also activates an atypical kinase known as mTOR, w</p><p>cancer cells, including colon cancer, activation of Gas by COX-2 derived pros</p><p>PKA-dependent regulation of multiple transcription factors and Gas and Gbg</p><p>such as b-catenin. See text for details.</p><p>www.sciencedirect.com PGE2</p><p>O</p><p>PLC-</p><p>Adenylyl</p><p>AxinGTP</p><p>s</p><p>PIP2DAGIP3cAMP, calcium/DG, cGMP, and calcium, respectively(Figure 1). Many of these kinases contribute to cancerprogression and metastasis [1722].</p><p>Small GTPases and MAPK cascades</p><p>In addition to the regulation of second messengers,GPCRs can control cell migration, survival, and growthby activating multiple mitogen activated protein kinase(MAPK) cascades. These include ERK1/2, JNK1-3,p38a-d MAPKs, and ERK5, which are a group of highlyrelated serine/threonine kinases that link cell surfacereceptors to transcription factors [23]. In general, whileRas GTPases regulate ERK1/2, small GTPases of theRho family, Rho, Rac, and Cdc42, control JNK and p38MAPKs by a distinct kinase cascade [24] (Figure 1).These MAPKs play key roles in cell proliferation and</p><p>PAK ERK</p><p>Ras</p><p>Ras GEF</p><p>PKC</p><p>ts </p><p>cyclase</p><p>-catenin</p><p>GSK3</p><p>[cAMP]</p><p>PKA</p><p>Nuclear events </p><p>PI3K</p><p>AKT</p><p>mTOR</p><p>Proteinsynthesis</p><p>[Ca2+]</p><p>Actinremodeling Nuclear</p><p>events</p><p>RAF</p><p>SurvivalCurrent Opinion in Cell Biology</p><p> results in the activation of multiple signaling pathways including second</p><p>) for Ras and Rho GTPases, MAP kinases, PI3Ks, and their numerous</p><p>s to normal cell growth, survival, differentiation, and migration, but</p><p>result in tumor initiation, progression, and metastasis. In general, most</p><p>nd Gai Ga subunits, which initiate intracellular signaling together with</p><p> converge in the nucleus to regulate the expression of growth promoting</p><p>nd c-JUN AP1 family members, YAP/TAZ, and c-MYC, among others. In</p><p> cell cycle proteins, and promote cell survival through inactivation of pro-</p><p>hich regulates protein synthesis, cell growth, and proliferation. In certain</p><p>taglandins promotes cell proliferation by multiple mechanisms, including</p><p>-initiated pathways controlling the accumulation of transcription factors</p><p>Current Opinion in Cell Biology 2014, 27:126135</p></li><li><p>128 Cell regulationmetastasis, and their deregulation is a frequent event inhuman malignancies. Hence, how GPCRs regulateMAPKs, particularly through Ras and Rho GTPases,has been explored under multiple physiological andpathological conditions.</p><p>Specifically, many GPCRs coupled to Gi activate Rac andJNK through the direct interaction of Gbg subunits withthe P-REX1/2 family of Rac guanine nucleotide exchangefactors (GEFs) [25,26]. Gaq activates Rho GTPasesthrough p63-RhoGEF and Trio [27]. Receptors coupledto Ga12 and Ga13 activate Rho by stimulating a family ofRho GEFs, comprised of p115, PDZRhoGEF and LARG[28]. The JNK cascade is activated downstream of Racand Cdc42 [24], which can mediate signaling from Gbgdimers and Ga12, Ga13, Gaq and Gai (reviewed in [4]).Activation of the ERK1/2 pathway by GPCRs is achievedin a highly cell-specific fashion (reviewed in [4]), pro-moted by Ras, tyrosine kinases, PI3Ks, PKCs, and/orarrestins. How GPCRs activate p38 and ERK5 is muchless clear, but in general these MAPKs are activatedprimarily by Gaq, Ga12/13, and Gbg dimers [4]. Activationof MAPK pathways stimulates the expression of growthpromoting early-immediate responsive genes, includingthose encoding the AP-1 family of transcription factors.MAPKs are involved in the regulation of both geneexpression and transactivating activity of AP-1 membersby a complex and not fully understood mechanism(Figure 1).</p><p>Activation of the PI3K, AKT, and mTOR pathway</p><p>Activation of the PI3KAKTmTOR pathway plays acentral role in cell metabolism, migration, growth andsurvival [29,30]. PI3K generates PIP3 inducing activationof AKT and mTOR [29,30]. PI3Kg exhibits restrictedtissue distribution and is activated by the direct interactionof its catalytic (p110g) and regulatory subunit (p101) withGbg subunits [31]. PI3Kg is involved in chemokine-induced migration of leukocytes, and plays significant rolesin innate immunity [32]. In cells lacking PI3Kg expression,GPCRs can utilize PI3Kb to stimulate PIP3 synthesis[33,34]. One of the most studied PI3K-regulated eventsis the activation of the kinases AKT and mTOR, whichphosphorylate multiple substrates involved in cellmigration, survival, and metabolism [33,34] (Figure 2).</p><p>Regulation of the Hippo signaling pathway</p><p>GPCRs involved in cell proliferation stimulate theactivity of the transcriptional co-activator YAP [35],which is a critical component of the Hippo signalingpathway that controls organ size in mammals [3639].YAP (and related TAZ), is active in proliferating cells, butcell confluence triggers the activation of the growth-inhibitory Hippo kinase cascade. This causes the acti-</p><p>vation of two kinases known as LATS1/LATS2, whichphosphorylate and thereby inhibit YAP [40]. GPCRslinked to Ga12/13 inhibit the activity of LATS, thus</p><p>Current Opinion in Cell Biology 2014, 27:126135 relieving YAP from LATS-dependent inhibition [35],while receptors activating Gas promote LATS activationthus inhibiting YAP [35]. Recent work in our laboratoryindicates that oncogenic mutations in the gene encodingGaq activate YAP by a mechanosensing pathway initiatedupon actin polymerization rather than by the inhibition ofthe Hippo pathway (unpublished results). YAP activationmay represent a key pro-tumorigenic pathway activatedby GPCRs, thereby representing a novel target for cancertreatment.</p><p>GPCR signal integration and crosstalk</p><p>While GPCRs can stimulate multiple diffusible second-messenger generating systems, their ability to promotenormal and aberrant cell proliferation often relies on thepersistent activation of PI3K/AkKT/mTOR, Ras and RhoGTPases, and MAPK cascades, thereby regulating theactivity of nuclear transcription factors and co-activators,such as JUN, FOS and YAP [35,41]. Additionally,arrestin proteins contribute to G protein-dependentand G protein-independent events, initiating signalingand regulating receptor internalization and degradation/recycling kinetics [42,43]. b-Arrestins are now believed toscaffold a wide variety of signaling complexes [44,45].Some b-arrestin-biased GPCR agonists initiate intracellu-lar signaling independently of the activation of hetero-trimeric G proteins [45]. By forming multimeric signalingcomplexes with ERK1/2 and JNK, b-arrestins can retainthese MAPKs in the cytosol, thus restricting their nucleartranslocation and leading to interaction with cytosolicsubstrates instead [45].</p><p>A more global view of the general systems by whichGPCRs exert their numerous physiological and patho-logical roles is necessary to appreciate the overall implica-tions to tumorigenesis. In particular, extensive cross-talkand co-regulation may occur between GPCR-initiatedand RTK-initiated signaling pathways and through re-ceptor transactivation [46,47]. Therefore, the final bio-logical outcome of GPCR activation results from theintegration of the network of GPCR-initiated bio-chemical responses in each cellular and environmentalcontext. Such systems level understanding may provide amolecular framework for the development of novelapproaches for therapeutic intervention in some of themost prevalent human diseases.</p><p>Viral GPCRsEarly studies of virally encoded oncogenes provided thefoundation of our current understanding of cancerbiology. At least seven human viruses, Epstein-Barr virus(EBV/HHV-4), hepatitis B virus (HBV), hepatitis C virus(HCV), human papilloma virus (HPV), human T-celllymphotropic virus (HTLV-1), and Kaposis associated</p><p>sarcoma herpes virus (KSHV/HHV-8), and Merkel cellpolyomavirus, contribute to 1015% of cancers [48,49].Surprisingly, many human viruses harbor open reading</p><p>www.sciencedirect.com</p></li><li><p>G protein, G protein-coupled receptor signaling in cancer OHayre, Degese and Gutkind 129Figure 2frames encoding GPCRs in their viral genomes, indicat-ing that these signaling circuits are required for replica-tive success [50]. For example, EBV encodes one GPCR(BILF1), and human cytomegalovirus (HCMV/HHV-5)expresses at least four GPCRs (US28, US27, UL33 and</p><p>Kaposis SarcomaAssociated Virus (KSHV/HHV-8)</p><p>GTP</p><p>q/11Adcy</p><p>Protein synthesis</p><p>PKC</p><p>GTP</p><p>12/13</p><p>Paracrine neop...</p></li></ul>

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