Molecular Signaling of Somatostatin Receptors

121

Ann. N.Y. Acad. Sci. 1014: 121–131 (2004). © 2004 New York Academy of Sciences.doi: 10.1196/annals.1294.012

Molecular Signaling of Somatostatin Receptors

HICHAM LAHLOU, JULIE GUILLERMET, MARYLIS HORTALA,FABIENNE VERNEJOUL, STÉPHANE PYRONNET, CORINNE BOUSQUET,AND CHRISTIANE SUSINI

INSERM U 531, IFR 31, CHU Rangueil, 31403 Toulouse Cedex 4, France

ABSTRACT: Somatostatin is a neuropeptide family that is produced by neu-roendocrine, inflammatory, and immune cells in response to different stimuli.Somatostatin acts as an endogenous inhibitory regulator of various cellularfunctions including secretions, motility, and proliferation. Its action is mediat-ed by a family of G-protein–coupled receptors (called sst1–sst5) that are widelydistributed in the brain and periphery. The five receptors bind the naturalpeptides with high affinity, but only sst2, sst5, and sst3 bind the short syntheticanalogs used to treat acromegaly and neuroendocrine tumors. This reviewcovers the current knowledge in somatostatin receptor biology and signaling.

KEYWORDS: somatostatin; receptors; signal transduction

SOMATOSTATIN AND SOMATOSTATIN RECEPTOR FAMILY

Since its discovery three decades ago, somatostatin has attracted much attentionbecause of its functional role in the regulation of a wide variety of physiologicalfunctions in the brain, pituitary, pancreas, gastrointestinal tract, adrenals, thyroid,kidney, and immune system. Its actions include inhibition of endocrine and exocrinesecretions, modulation of neurotransmission, motor and cognitive functions, inhibi-tion of intestinal motility, absorption of nutrients and ions, and vascular contractility.In addition, the peptide controls the proliferation of normal and tumor cells. Thebiological effects of somatostatin are mediated through high-affinity plasma mem-brane receptors, which are widely distributed throughout many tissues ranging fromthe central nervous system to the pancreas and gut, and also in pituitary, kidney,thyroid, lung, and immune cells.1,2 Recently, the somatostatinergic system has beenextended by the discovery of cortistatin, which shares 11 of the 14 amino acids ofsomatostatin-14 and is predominantly expressed in the cortex and hippocampus.However, the nucleotidic sequence and chromosomal localization of both peptidesclearly indicate that they are the products of two separate genes.3

Somatostatin receptors (sst1-sst5) are encoded by five genes localized on differ-ent chromosomes. Four of these genes are intronless, the exception being sst2, whichis alternatively spliced in rodents to generate two isoforms, named sst2A and sst2B,which diverge in their C-terminal sequence. The sst subtypes belong to the family of

Address for correspondence: Dr Christiane Susini, INSERM U531, IFR 31, CHU Rangueil,31403 Toulouse Cedex 4, France. Voice: 33 5 61 32 24 07; fax: 33 5 61 32 24 03.

[email protected]

122 ANNALS NEW YORK ACADEMY OF SCIENCES

G-protein–coupled receptors with seven transmembrane-spanning domains(GPCRs) and present a high similarity of sequence (39–57%). They all bind soma-tostatin 14, somatostatin 28, and cortistatin with similar high affinity (nM range).Only sst5 displays a 10-fold higher affinity for somatostatin 28. However, ssts showmajor differences in their affinities for somatostatin peptide analogs, such asoctreotide and lanreotide, in clinical use for the medical treatment of acromegaly andneuroendocrine tumors. These analogs exhibit low affinity for sst1 and sst4(≥ 1 µM), whereas they bind sst2, sst5 with a high affinity, and sst3 with moderateaffinity.4

SIGNAL TRANSDUCTION PATHWAYS

Using recombinant ssts expressed in various eukaryotic cells as well as specificsomatostatin receptor subtype analogs, the intracellular signal transduction machin-ery implicated in somatostatin action has begun to be elucidated (TABLE 1). Asreported for other GPCRs, the binding of somatostatin to endogenous receptors trig-gers a wide variety of pertussis-toxin sensitive and insensitive G-protein–dependentintracellular signals, each receptor subtype being coupled to multiple intracellulartransduction pathways. Activation of these pathways leads to a number of cellularconsequences including modulation of ion secretion, regulation of gene expression,cell proliferation, cell adhesion, and apoptosis.

All five ssts are functionally coupled to inhibition of adenylate cyclase via a per-tussis-toxin sensitive protein (Gαi1-3), and this effect may participate in the anti-secretory action of somatostatin. However, somatostatin-induced inhibition ofpeptide secretion mainly results from a decrease in intracellular Ca2+. This isachieved by either opening K+ channels and secondarily inhibiting voltage-depen-dent Ca2+ currents or closing voltage-dependent Ca2+ channels. In neuronal andneuroendocrine cells, somatostatin and analogs activate K+ channels via Giα2-3, thusresulting in hyperpolarization of the plasma membrane. Somatostatin regulates sev-eral voltage-gated K+ channels (delayed-rectifier K+, inward-rectifier K+ channels,Ca2+-activated K+ channels, and A-type K+, and M-type K+ currents). Sst2, sst3,sst4, and sst5 activate inward-rectifying K+ channels in Xenopus oocytes, sst2 cou-pling being the most efficient.5 However, sst1 may be involved in inhibition of K+

currents in cortical oligodendrocytes.6 Somatostatin also decreases Ca2+ influx bydirectly inhibiting high voltage-dependent Ca2+ channels via Gοα2/β1/γ3. The peptideregulates different voltage-dependent Ca2+ currents, including L-type, N-type, andT-type currents. Using receptor subtype-specific analogs, it has been demonstratedthat sst2, sst5, and sst1 negatively couple to voltage-dependent calcium channels inmouse pituitary cells and in rat insulinoma 1046-38 cells, respectively.7,8 In addi-tion, ssts can induce an increase in Ca2+ mobilization as a result of phospholipase Cactivation via pertussis-toxin dependent and independent G-proteins, albeit at ago-nist concentrations higher than 1 nM.4 Such activation of phospholipase C may beinvolved in somatostatin-mediated stimulation of smooth muscle contraction. In-deed, in intestinal smooth muscle cells, sst3 stimulates D-myo-inositol-1,4,5-tris-phosphate (IP3) formation, Ca2+ release, and contraction via Gβγ subunit-mediatedactivation of PLC-β3.9

123LAHLOU et al.: MOLECULAR SIGNALING OF SOMATOSTATIN RECEPTORS

In enteric endocrine cells and hepatic cells, which express endogenous ssts,somatostatin inhibits the activity of the ubiquitously expressed Na-H exchangerNHE1. By allowing Na+ to enter the cell in exchange for H+, NHE1 activity partic-ipates in intracellular pH homeostasis and cell volume regulation and is associatedwith increased cell proliferation. When heterologously expressed in fibroblasts, sst1,sst3, and sst4, but not sst2 and sst5, mediate inhibition of NHE1 by a GTP-dependentbut Gi-independent mechanism. However, when expressed in CHOK1 cells, sst4 canstimulate Na+/H+ exchange in a pertussis-toxin–sensitive manner in agreement withthe proliferative effect of sst4 observed in this cellular model.10 Recently, consensusmotifs of T/S/P-V within the intracellular domain 2 and of Q-Q/R within the intra-cellular domain 3 have been demonstrated to confer a Gi-independent coupling ofGPCRs to NHE1. Interestingly, these motifs are present in NHE1-coupled sst1, -3,and -4 but absent in sst2 and -5, which do not signal to NHE1.11,12 The G-proteincoupling sst to NHE1 remains to be identified but Gα12, which is known to inhibitNEH1, is a good candidate.12 NEH1 acts downstream of the small GTPase Rho,which plays a crucial role in regulating cytoskeletal organization. NEH1 is phos-phorylated by Rho-associated kinase ROCK. Moreover, through its direct associa-tion with the ERM (erzin/radixin/moesin) family of actin-binding proteins, NEH1acts as a plasma membrane anchor for actin filaments to control the assembly of

TABLE 1. Somatostatin receptor signaling

Transduction pathways sst1 sst2 sst3 sst4 sst5

Adenylate cyclase ↓ ↓ ↓ ↓ ↓Phospholipase C ↑ ↑ ↑ ↑ ↑/↓Phospholipase A2 ↓ ↓ ↑Tyrosine phosphatases ↑ ↑ ↑ ↑ ↑

SHP-1 ↑SHP-2 ↑ ↑

Tyrosine kinases

-c-src ↑ ↑-JAK2 ↑

Pi-3 kinase ↑ ↑ ↑Nitric oxide synthases

-nNOS ↑-eNOS ↓

Ca2+ channels ↓ ↓ ↓K+ channels ↓ ↑ ↑ ↑ ↑Na+/H+ exchange ↓ ↓ ↓/↑MAP kinases

- ERK ↓/↑ ↓/↑ ↓ ↑ ↓- p38 ↑ ↑- JNK ↑


stress fibers and focal adhesions.13 Recently, in CCL39 fibroblasts stably expressingsst1 or sst2, it was reported that sst1, but not sst2, inhibits the activation of Rho, theassembly of focal adhesions and actin stress fibers, and cell migration.14

Somatostatin and analogs activate a number of protein phosphatases includingserine/threonine phosphatases, the Ca2+-dependent phosphatase, calcineurin, theSH2 domains-containing nontransmembrane tyrosine phosphatases (PTP)s SHP-1and SHP-2, and the receptor-like PTP, r-PTPeta,15–18 Somatostatin-induced activa-tion of calcineurin has been observed in insulin-secreting beta cells and may partic-ipate in sst-mediated inhibition of exocytosis.16 Sst1-5 stimulate a tyrosinephosphatase activity via a PTX-sensitive G-protein when expressed in NIH 3T3fibroblast or CHO cells.19–23 Antiproliferative actions of somatostatin have beenshown to result partly from translocation and/or activation of SHP-1 in various cellsystems expressing endogenous sst2.18,24–26 In CHO cells expressing sst2 (CHO/sst2), activation of sst2 by analogs transiently increases the formation of sst2-SHP-1-Giα3 complexes, leading to activation of SHP-1.18 We recently identified the Srctyrosine kinase and SHP-2 tyrosine phosphatase as sst2-associated molecules actingupstream of SHP-1. In CHO/sst2, Src and SHP-2 are both associated with sst2. SHP-2 directly associates with phosphorylated tyrosine 228 and 312, which are located insst2 ITIMs (immunoreceptor tyrosine-based inhibitory motifs, one in the third intra-cellular loop, L-C-Y228-L-F-I, and the second in the C-terminal tail, I-L-Y312-A-F-L). Upon sst2 activation by somatostatin, Src becomes activated by a Gβγ-dependentmechanism. In turn, Src activation leads to sst2 hyperphosphorylation and SHP-2activation. Then, dephosphorylation of signal relay molecules permits SHP-1recruitment and activation.27 The activated enzyme rapidly dissociates from sst2 tobe recruited by its substrates such as activated growth factor receptors, thus leadingto their dephosphorylation and negative regulation of mitogenic signaling. SHP-1activation results in cell cycle arrest, which depends on the induction of the cyclin-dependent kinase inhibitor p27Kip1, on the inhibition of cyclin E-cdk2 kinase activ-ity, and on the accumulation of the hypophosphorylated Rb protein.28 Somatostatin-activated SHP-2 has also been observed in CHO-K1 cells overexpressing sst1. Inthese cells, somatostatin induces a transient activation of SHP-2, which is involvedin the activation of the Ras/Raf-1/ mitogen-activated protein kinases (MAPK) ERKpathway, leading to increased expression of cyclin-dependent inhibitor p21cip/Waf1

and to cell cycle arrest.29 SHP-2 is also implicated in sst2-mediated signal transduc-tion in glioma cells, which express endogenous sst2. Stimulation of SHP-2 results indephosphorylation of activated receptors for EGF and PDGF, and, as a consequence,ERK1/2 are dephosphorylated.17 In PC Cl3 thyroid cells, activation of r-PTP eta bysomatostatin is involved in somatostatin-mediated inhibition of the phosphorylation,ubiquitination, and proteasome degradation of the cyclin-dependent kinase inhibitorp27kip1, which, in turn, leads to cell proliferation arrest.23

The MAPK ERK pathway is an important mediator of somatostatin-induced cellgrowth regulation. However, this pathway is differently regulated according to thesst subtype and cell environment. Sustained activation of ERK1/2 pathway is gener-ally related to S phase entry and growth-promoting actions of growth factors, cyto-kines, and ligands for GPCRs. Indeed, the human sst4, stably expressed in CHO-K1cells, mediates proliferative activity of somatostatin by a mechanism involving asustained protein kinase C-mediated activation of the ERK1/2 pathway.10 Such aproliferative effect of somatostatin is also observed with human B lymphoblasts,


which express the sst2 subtype.30 However, in both reports, the stimulatory effect isobserved at a high peptide concentration (≥100 nM) and in serum-free medium cellculture conditions, and it may be partly related to the stimulatory effect of soma-tostatin on phospholipase β. Conversely, in neuroblastoma and small cell lung cancercells, sst1 and/or sst2 somatostatin analogs inhibit ERK activity stimulated by serumor growth factors, and this effect is related to the antiproliferative action of thesepeptides.31 In Eahy926 endothelial cells, which express only sst3, somatostatininhibits VEGF-induced ERK1/2 activation and cell proliferation.32 Such an inhibi-tion of ERK1/2 is also observed in CHO cells expressing sst5 and in neuroblastomacells treated with an sst5-specific somatostatin analog.31,33 Sst5-mediated inhibitionof ERK1/2 results from a dephosphorylation cascade including inhibition of guany-late cyclase and inhibition of cGMP-dependent protein kinase G, and leads to cellgrowth inhibition.33 On the other hand, when expressed in CHO cells, sst1 and sst2transiently activate MAPK ERK1/2, and this pathway is implicated in the expressionof p21Cip1 or p27Kip1 cyclin-dependent kinase inhibitors and in the antiproliferativeeffect of somatostatin or analogs.29,34,35 Transient activation of ERK1/2 by soma-tostatin is also observed in hematopoietic cells, which endogenously express sst2.36

It is now well demonstrated that differentiation or growth inhibition may also be aconsequence of ERK1/2 activation. For instance, nerve growth factor-induced andhepatocyte growth factor-induced activation of ERK1/2 has been shown to result inNIH3T3 and HepG2 cell cycle arrest, respectively.37 Transforming growth factor-beta blocks the proliferation of different cell lines through a rapid and transientactivation of ERK1/2.38 A possible explanation for this discrepancy could be adifferent cellular response to transient or sustained ERK activation. Thus, the bio-logical outcome of ERK1/2 activation is dependent on cell types, extracellular fac-tors and their receptors, but also on the amplitude and duration of ERK1/2 activation.Recently, it was shown that the immediate early gene products, such as the proto-oncogene product c-Fos, that control cell cycle progression, function as a sensor forERK1/2 signal duration. When ERK1/2 activation is transient, c-Fos is transcription-ally induced within minutes of stimulation, but the protein is unstable and degraded.However, when ERK1/2 activation is sustained, c-Fos is hyperphosphorylated andactive, its transcriptional activity controlling the biological outcome.39 Althoughboth sst1 and sst2 activate ERK1/2, they signal through two different pathways. Sst1activates ERK1/2 through the c-src/SHP-2/phosphatidylinositol 3-kinase (PI3K)/Ras/Raf-1/MEK pathway, whereas sst2-dependent activation of ERK1/2 requiresSHP-1/SHP-2/PI3K/Rap1 and Ras/B-Raf/MEK.29,35 MAPK phosphorylates andregulates several proteins including transcription factors and cytoplasmic proteinssuch as phospholipase A2, which hydrolyzes triglycerol to form arachidonic acid.Sst4-induced activation of ERK1/2 leads to phosphorylation and activation of phos-pholipase A2 and the transcription factor STAT3, which may be part of the prolifer-ative response to somatostatin mediated by sst4.34,40 However, arachidonic acidrelease may also partly account for the somatostatin-mediated regulation of some K+

currents observed in rat hippocampal neurons that predominantly express sst4.41 Inrat pituitary tumor GC cells, sst1 and sst2 are negatively coupled to phospholipaseA2, leading to a decrease in arachidonic acid release, and this pathway may be in-volved in somatostatin control of GH secretion in GC cells.42 The other MAPK, p38and c-Jun N-terminal kinase (JNK), which can also be related to cell growth arrest,are also regulated by somatostatin. p38 is activated by somatostatin in CHOK1 cells


expressing sst2, and this pathway is involved in the antiproliferative effect of soma-tostatin in this model.43 Somatostatin activates JNK via Gα12 in COS cells express-ing sst5.44

GPCRs have no intrinsic tyrosine kinase activity, and recruitment and activationof Src family kinases are now known to play a role in GPCR-mediated Ras-depen-dent activation of mitogenic signaling pathways.45 Somatostatin and analogs havebeen reported to activate tyrosine kinases. Sst1, sst2, and sst4 activate c-src, and thiseffect is involved in somatostatin-induced ERK activation.35,46,47 Src is activated byeither dephosphorylation of its C-terminal regulatory tyrosine or engagement of theSH2 and SH3 domains with heterologous proteins or through direct binding of Srcto β-arrestin by a G-protein βγ-dependent mechanism.45 β-arrestin has been shownto be recruited by activated sst2 receptors.48 We found that somatostatin-activatedsst2 stimulates Src by a βγ-dependent mechanism.27 Thus, one possibility is that insst2 signaling, somatostatin-mediated βγ-dependent recruited β-arrestin participatesin Src activation. The tyrosine kinase JAK2 is involved in mitogenic cell responses.JAK2 belongs to the family of JAK tyrosine kinases that bind to members of thecytokine receptor family and are activated by transphosphorylation after ligand bind-ing to these receptors. The activated JAK2, in turn, phosphorylates tyrosines withinitself and the associated receptors, forming high-affinity binding sites for a varietyof signaling molecules including signal transducers and activators of transcription(STAT), which regulate the expression of a variety of cytokine-dependent genes.However, JAK2 may also display antimitogenic effects when functionally associatedwith a receptor, which negatively regulates cell growth. In rat pancreatic cancerAR42J cells stably expressing the 210 amino-acid FGF-2 isoform (HMW FGF-2),we recently demonstrated that a ternary complex sst2/JAK2/SHP-1 is present inthese cells, which highly express endogenous sst2. Treatment of AR42J cells withsomatostatin analog induces rapid activation of both JAK2 and SHP-1, which isimplicated in the sst2-mediated inhibition of the HMW FGF-2 mitogenic effect.49

Nitric oxide synthases (NOSs), expressed as cytokine-inducible (iNOS), endo-thelial (eNOS), and neuronal (nNOS) isozymes, oxidize L-arginine to nitric oxide(NO) and citrulline, thereby controlling NO distribution and concentrations in high-er eukaryotes. NO is now recognized as an important signaling molecule that isinvolved in the regulation of many physiological functions including neurotransmis-sion, cell differentiation and proliferation, endothelial cell permeability, and plateletaggregation. Inhibition of mitogen-induced cell proliferation triggered by the NOsignaling system is well documented in several normal and tumor cell systems suchas vascular and airway smooth muscle cells, glomerular mesangial cells, and pancre-atic tumor cells. We recently identified nNOS as a novel SHP-1 substrate critical forsst2-induced cell growth arrest. Following somatostatin analog-mediated activationof SHP-1, the enzyme rapidly recruits nNOS; tyrosine dephosphorylates and acti-vates it. The resulting NO activates guanylate cyclase and inhibits cell proliferation.Similar results are observed in mouse pancreatic acini, which express endogenoussst2. By contrast, in acini from viable moth-eaten mev/mev mice, which expressinactive SHP-1, somatostatin has no effect on nNOS activity.50 NO plays a pivotalrole in angiogenesis, and eNOS activity seems to account for the majority of NO pro-duced by endothelial cells. Inhibition of sst3-mediated eNOS activity is involved inthe antiangiogenic activity of somatostatin observed in vitro, through the regulationof endothelial cell proliferation, and in vivo, through inhibition of the angiogenic


response induced by Kaposi’s sarcoma cell products in matrigel sponges implantedsc into mice.32

Two main signaling pathways initiate the apoptotic program in mammalian cells.The cell-extrinsic pathway triggers apoptosis in response to engagement of tumornecrosis factor (TNF) family death receptors by their ligands. Members of the TNFreceptor family include TNF-RI for TNFα, Fas or CD95 for FasL, and TRAIL-RI/DR4 or TRAIL-R2/DR5 for TNF-related apoptosis inducing ligand (TRAIL). Uponligand binding, these receptors trimerize and activate the initiator caspases, includ-ing caspase-8. Caspases are cysteine proteases that are constitutively expressed inthe cytosol as proenzymes and are activated to mature proteases by cleavage. Theinitiator caspases, in turn, activate the executioner caspases-3, -6, and -7, which areresponsible for the cell damage observed during apoptosis. On the other hand, thecell-intrinsic pathway triggers apoptosis in response to DNA damage, loss of surviv-al factors, or other types of cell distress. This pathway involves activation of the pro-apoptotic Bcl-2 gene superfamily, which engages the mitochondria to cause therelease of apoptogenic factors including cytochrome c into the cytosol, which, inturn, results in the activation of the executioner caspases-3, -6, and -7. It has beendocumented that somatostatin promotes apoptosis in normal and tumor cells.51–53 Inaddition, SHP-1 has been shown to be a critical component for somatostatin-medi-ated induction of cell acidification and apoptosis in breast carcinoma MCF-7 cells.54

Sharma et al.55 reported that in CHO-K1 clones transfected with each of the five sst1–5 subtypes, somatostatin-induced apoptosis is signaled uniquely through humansst3 and is associated with a dephosphorylation-dependent conformational changeof p53 as well as induction of Bax. However, when expressed in human pancreaticcancer BxPC-3 cells, which have lost sst2 endogenous expression, sst2 also triggersapoptosis in a SHP-1–dependent manner. Interestingly, sst2 sensitizes cells to apo-ptosis induced by TNFα and by TRAIL or CD95L. Sst2-dependent activation andcell sensitization to death ligand-induced apoptosis involve the activation of theexecutioner caspases. Strikingly, sst2 affected both death ligand and mitochondrialpathways by upregulating the expression of the TRAIL and TNFα receptors, DR4and TNFRI, respectively, and by downregulating the expression of the anti-apoptoticmitochondrial Bcl-2 protein.56

Like other GPCRs, some somatostatin receptors can initiate their ligand-inducedsignaling cascades by receptor dimerization. Dimerization of somatostatin receptorswas first reported by photobleaching fluorescence resonance energy transfer for sst5,which exists as a monomer in the basal state and oligomerizes after ligand activa-tion.57 Sst2 and sst3 can also homodimerize, whereas sst1 does not formhomodimers.58,59 Sst can also heterodimerize when coexpressed with either othersomatostatin receptor subtypes or other GPCRs. Indeed, sst5 can heterodimerizewith sst1 but not with sst4.57 Heterooligomerization has been shown to alter ligandbinding affinity and/or signaling efficacy of GPCRs. Sst2 heterodimerizes with sst3,and this results in inactivation of sst3 receptor function.59 Such a functional inacti-vation of sst3 by heterodimerization with sst2 may provide an explanation for theabsence of sst3 receptor binding in some tissues, which highly express sst3. More-over, sst also heterodimerizes with other GPCRs. Sst2 heterooligomerizes with theµ opiod receptor (MOR1) when coexpressed in human embryonic kidney cells 293.Sst2-MOR1 heterooligomerization does not affect ligand binding or coupling prop-erties, but it promotes cross-modulation of phosphorylation, internalization, and de-


sensitization of both receptors.60 When coexpressed with the dopamine D2 receptor,sst5 can form heterooligomers that display pharmacological properties distinct fromthose of either of the separate receptors.61 Thus, heterodimerization would have im-portant functional consequences, including change in binding affinity and functionalactivity and initiation of signal transduction pathways not triggered by individualreceptors, and therefore represents a novel regulatory mechanism that could promotesignaling specificity within the sst receptor family, but also more generally in theGPCR family.

In conclusion, ssts activate a variety of intracellular signaling mechanisms andthereby regulate a complex array of cellular functions. Moreover, oligomerization ofsst is a growing field of research that adds a previously unappreciated level of com-plexity to sst function and regulation. Oligomerization may generate new pharmaco-logical properties for some receptor combinations and thus provide a novelregulatory mechanism that could alter the signaling properties and the trafficking ofthe GPCRs concerned. Novel approaches for therapeutic drug design and discoverymay arise from the identification of sst oligomers.

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Molecular Signaling of Somatostatin Receptors

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