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

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    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

    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.

    Second messenger generating systems

    GPCR stimulation triggers the activation of heterotri-meric G proteins as GTP replaces GDP on the Ga

    Current Opinion in Cell Biology 2014, 27:126135 www.sciencedirect.comNovel insights into G protein ansignaling in cancerMorgan OHayre, Maria S Degese an

    G protein-coupled receptors (GPCRs) play a central role in

    signal transmission, thereby controlling many facets of cellular

    function. Overwhelming evidence now implicates GPCRs, G

    proteins and their downstream signaling targets in cancer

    initiation and progression, where they can influence aberrant

    cell growth and survival, largely through activation of AKT/

    mTOR, MAPKs, and Hippo signaling pathways. GPCRs also

    play critical roles in the invasion and metastasis of cancer cells

    via activation of Rho GTPases and cytoskeletal changes, and

    angiogenesis to supply the tumor with nutrients and provide

    routes for metastasis. Lastly, GPCRs contribute to the

    establishment and maintenance of a permissive tumor

    microenvironment. Understanding GPCR involvement in

    cancer malignancy may help identify novel therapeutic

    opportunities for cancer prevention and treatment.


    Oral and Pharyngeal Cancer Branch, Dental and Craniofacial Research,

    National Institutes of Health, Bethesda, MD 20892, USA

    Corresponding author: Gutkind, J Silvio (

    Current Opinion in Cell Biology 2014, 27:126135

    This review comes from a themed issue on Cell regulation

    Edited by Jeffrey L Benovic and Mark von Zastrow

    Available online XXX

    0955-0674/$ see front matter, Published by Elsevier Ltd.

    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

    ScienceDireG protein-coupled receptor

    J Silvio Gutkind

    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.

    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.

    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

  • G protein, G protein-coupled receptor signaling in cancer OHayre, Degese and Gutkind 127


    linsinnFigure 1






    Adenylylcyclase LARG

    PRG p63





    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

    PI3KRas GEFRac GEF

















    JNK p38


    Nuclear evenActin


    Activation of growth and survival pathways by GPCRs. Stimulation of GPCRs

    messenger generating systems, guanine nucleotide exchange factors (GEFs

    downstream cytosolic and nuclear targets. This signaling network contribute

    aberrant activation of GPCRs/G proteins and their downstream targets can

    mitogens acting on GPCRs stimulate Gaq/11, while others activate Ga12/13 a

    multiple pathways regulated by Gbg subunits. In turn, these signaling routes

    genes by the prolonged stimulation of transcription factors including c-FOS a

    parallel, activation of PI3K and AKT can induce cell proliferation by regulating

    apoptotic proteins. AKT also activates an atypical kinase known as mTOR, w

    cancer cells, including colon cancer, activation of Gas by COX-2 derived pros

    PKA-dependent regulation of multiple transcription factors and Gas and Gbg

    such as b-catenin. See text for details. PGE2






    PIP2DAGIP3cAMP, calcium/DG, cGMP, and calcium, respectively(Figure 1). Many of these kinases contribute to cancerprogression and metastasis [1722].

    Small GTPases and MAPK cascades

    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



    Ras GEF








    Nuclear events






    Actinremodeling Nuclear



    SurvivalCurrent Opinion in Cell Biology

    results in the activation of multiple signaling pathways including second

    ) for Ras and Rho GTPases, MAP kinases, PI3Ks, and their numerous

    s to normal cell growth, survival, differentiation, and migration, but

    result in tumor initiation, progression, and metastasis. In general, most

    nd Gai Ga subunits, which initiate intracellular signaling together with

    converge in the nucleus to regulate the expression of growth promoting

    nd c-JUN AP1 family members, YAP/TAZ, and c-MYC, among others. In

    cell cycle proteins, and promote cell survival through inactivation of pro-

    hich regulates protein synthesis, cell growth, and proliferation. In certain

    taglandins promotes cell proliferation by multiple mechanisms, including

    -initiated pathways controlling the accumulation of transcription factors

    Current Opinion in Cell Biology 2014, 27:126135

  • 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.

    Specifically, many GPCRs c


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