The many faces of the guanine-nucleotide exchange factor trio.

2012·0.39 MB·English

by  van Rijssel, Jos

CellAdhesion&Migration6:6,482–487;November/December2012;G2012LandesBioscience
The many faces of the guanine-nucleotide exchange factor trio
Jos van Rijssel and Jaap D. van Buul*
DepartmentofMolecularCellBiology;SanquinResearchandLandsteinerLaboratory;AcademicMedicalCenter;UniversityofAmsterdam;Amsterdam,theNetherlands
Small Rho-GTPases are enzymes that domainand aC-terminal serine/threonine
areboundtoGDPorGTP,which kinasedomain(Fig.1).4-8UsingDomPred
determines their inactive or active state, Protein Domain Prediction Server (freely
respectively. The exchange of GDP for available at http://bioinf.cs.ucl.ac.uk/
GTP is catalyzed by so-called Rho- dompred) and based on the protein
guanine nucleotide exchange factors sequence, we predict that Trio has nine
(GEFs). Rho-GEFs are characterized by spectrin-repeatsattheN-terminus.Shortly
a Dbl-homology (DH) and adjacent afterthediscoveryofTrio,acloselyrelated
Pleckstrin-homology (PH) domain that protein was identified that was named
serves as enzymatic unit for the GDP/ Kalirin.9-11 Trio and Kalirin share 68%
GTPexchange.Rho-GEFsshowdifferent nucleotide and 65% amino acid sequence
GTPase specificities, meaning that a identity, but whereas Trio is ubiquitously
particular GEF can activate either mul- expressed, Kalirin expression is mainly
tiple GTPases or only one specific confined to the central nervous system.1,10
GTPase. We recently reported that the Surprisingly, the N-terminal GEF unit is
Rho-GEF Trio, known to be able to almostidenticalbetweenthetwoproteins,
exchange GTP on Rac1, RhoG and showing 92% homology at the protein
RhoA, regulates lamellipodia formation level, whereas the C-terminal GEF unit
to mediate cell spreading and migration shows 67% homology.
in a Rac1-dependent manner. In this
commentary, we review the current Isoforms of Trio
knowledge of Trio in several aspects of
cell biology. Several isoforms of both Kalirin and Trio
have been identified. For both proteins, a
singlegeneisresponsiblefortheexpression
Introduction of Trio and Kalirin. However, due to
alternativesplicingandtheuseofdifferent
The Rho-GEF Trio was originally iden- promoters, several isoforms are
Keywords: Trio, Rac1, RhoG,
tified in 1996 as a binding partner of the formed.12,13 Kalirin-7 (also known as
lamellipodia, Rho-GEF
transmembrane tyrosine phosphatase Duo), -9 and -12 are expressed in the
Submitted: 03/22/12
LAR.1 Trio is a large protein of 350 kD brain and differ in length at their
Revised: 06/14/12 that harbors three domains with putative C-terminus.13 Several Trio isoforms, Trio
enzymatic activity, hence the name Trio. A, B and D, are strongly expressed in the
Accepted: 07/09/12
Trio encodes two Dbl-homology- brain and during development, whereas
http://dx.doi.org/10.4161/cam.21418
Pleckstrin-homology (DH-PH) Rho-GEF Trio C, also known as Solo/Trio8, is
*Correspondenceto:JaapD.vanBuul; units with different specificities. The N- exclusively expressed in the cerebel-
Email:[email protected] terminal DH-PH unit (TrioD1) mediates lum.12,14 All these splice variants include
GDP to GTP exchange on Rac1 and the N-terminal SEC14 and spectrin-
Commentaryto:vanRijsselJ,HoogenboezemM,
RhoG, whereas the C-terminal DH-PH repeats as well as the first DH-PH GEF
WesterL,HordijkPL,VanBuulJD.TheN-terminal
unit (TrioD2) activates RhoA.1-3 In addi- domain. A fifth isoform, Trio E, has been
DH-PHdomainofTrioinducescellspreading
andmigrationbyregulatinglamellipodia tion to the two GEF units, Trio also found in neuroblastoma cells and com-
dynamicsinaRac1-dependentfashion.PLoS includes an N-terminal putative lipid- prises the C-terminal GEF unit including
One2012;7:e29912;PMID:22238672;http://dx. transfer SEC14 domain, several spectrin- the kinase domain.12 Interestingly, a
doi.org/10.1371/journal.pone.0029912
repeats, two SH3-domains, an Ig-like sixth isoform named Tgat expresses the
482 CellAdhesion&Migration Volume6Issue6
COMMENTARY
Figure1.SchematicrepresentationofthestructureofRho-GEFsTrioandKalirin.TrioandKalirinbothexpresstwoDH-PHunits(green/red)andaserine-
kinasedomain(yellow).BothDH-PHunitsareflankedbyaSH3domain(lime/rose).TrioandKalirinharboraSEC14domain(royalblue)andspectrin-
repeats(skyblue)attheN-terminus.
C-terminalGEFunitonlyandisfoundin upon phosphorylation, Trio shifted to a Dbs,aretheonlyRho-GEFsinthefamily
patients with adult T-cell leukemia.15 more detergent-insoluble fraction.6 This of.80Rho-GEFmembersthatcomprise
indicates that Trio tyrosine phosphoryla- a SEC14 homology domain (Fig.1).27
Trio and Regulatory Mechanisms tion may trigger its interaction with the Proteins encompassing a SEC14 domain
actin cytoskeleton. However, it remains are widely expressed in plants, yeast,
As mentioned above, Trio is a large unclear if FAK affects the GEF activity of invertebrates and mammals, suggesting
protein that harbors next to the two Trio. that this domain is highly conserved.28
GEF and kinase domains several other Triointeractionpartners.Althoughthe SEC14 domains, also known as CRAL-
domains that may be involved in protein molecular mechanism of the activation of TRIO domains, were shown to mediate
or lipid interaction. Up to now, the the TrioD1 GEF domain is thus far the interaction between proteins and
mechanisms by which the individual unclear, its ability to activate Rac1 was specific phospholipids,8,29,30 such as
domains of Trio are activated and the showntoberegulatedbyinteractionswith PtdIns, PtdCho, PtdSer and a number of
functional consequences of this for Trio severalproteins.Rac1activationbyTriois different phosphorylated forms of PtdIns.
as a single protein are unclear. In this negatively regulated by interactions with Work by the group of Whitehead showed
section we will discuss the potential the F-actin capping protein CARMIL,18 thatremovaloftheSEC14domainofDbs
contribution of phosphorylation, inter- the motor protein Myosin II19 and the F- induced Dbs distribution to the periphery
and intra-molecular interactions and pres- actin binding protein Tara.20 In contrast, of the cell, whereas full length Dbs was
ence of two GEF domains with different association of the integral membrane found in peri-nuclear regions and co-
specificities. protein Kidins220/ARMS (kinase-D- localized with Golgi markers.31 Thus, the
Trio and phosphorylation. Our recent interacting substrate of 220 kDa/ankyrin SEC14 domain in Rho-GEFs may pro-
work suggests that during cell spreading repeat-rich membrane spanning) with the mote membrane targeting and thereby
Trio is activated upon the engagement of spectrin-repeats of Trio was demonstrated determine local Rho-GEF activity. The
integrins,inparticularintegrinβ1,sincein topromote Rac1activation.21 In addition, authors furthermore showed that the
our studies the cells were plated on the F-actin cross-linker protein Filamin SEC14 homology domain forms intracel-
fibronectin-coated surfaces in serum-free interacted with the PH-domain of the lularcontactswiththePH-domainofDbs.
conditions.16ResearchbythegroupofDer TrioD1 GEF unit and was required for Next, they showed that these contacts
showed that for theexchange factor Vav1, TrioD1-induced membrane dynamics.22 must be released to achieve full trans-
tyrosine phosphorylation by Lck is crucial In another study by Bellanger and collea- formation activity by Dbs.31 Whether the
for its GEF function in vitro.17 However, gues, they showed that the PH domain of SEC14 domain of Trio plays a similar
although Trio harbors several tyrosine TrioD1 is involved both in regulating the regulatory role in the activity of the N-
residues, it is not known if tyrosine catalytic activity of TrioD1 and in deter- terminal DH-PH domain of Trio is
phosphorylation is required for Trio- mining the sub-cellular localization of its unknown.
mediated GTP exchange. associated DH domain.23 Thus, the N- Trioandthespectrin-repeats.Spectrin-
Medley and colleagues showed that the terminal PH domain of Trio may serve as repeats are three-helix bundle structures
kinase domain of Trio, known to interact a cytoskeletal targeting signal. Since Rac1 that occur in many different proteins,
withLAR,isconstitutivelyphosphorylated has also been shown to bind to the actin- either as single copies, for Dbs, or in
on tyrosine residues.6 The levels of binding protein Filamin,24-26 Filamin may tandem repeats, for Trio and Kalirin.32
phosphorylation were further increased function as a scaffold for Trio-mediated These repeats can act in a structural way,
when FAK was co-expressed. Trio inter- Rac1 activation in a similar manner as has by coordinating cytoskeletal interactions
acted with FAK through two distinct beenreportedfortheinteractionoffilamin with high spatial precision, as well as an
regions: the SH3-Ig-like region and the with the GEF Vav2.26 intermediary for interactions with several
serine/threonine kinase domain (Fig.1). Trio and the SEC14 domain. Trio, regulatory proteins.32 For Kalirin, it is
The authors furthermore showed that together with the Rho-GEFs Kalirin and known that the spectrin-repeats bind to
www.landesbioscience.com CellAdhesion&Migration 483
the cytosolic part of peptidylglycine a- activity of Rac1 and RhoA are required at ROBO18,57 and the NGF receptor.21,37 In
amidating mono-oxygenase (PAM).10 the same location but not at the same addition, Trio was demonstrated to be an
Later, PAM was also found to interact time. Recently, it became clear that Rac1 essential regulator of skeletal muscle
withthespectrin-repeatsofTrio.33PAMis andRhoAarebothactivatedattheleading development.51,58,59 Mice deficient for
asecretory granule membrane protein and edge of a migrating cell.40,41 Using bio- Trio died between embryonic day E15.5
overexpression results in reduced filopodia sensor techniques for Rac1 and RhoA and birth and showed, besides aberrant
and cortical actin in AtT-20 cells.34,35 revealed that first RhoA and then Rac1 is organization of the hippocampus and
Recently, a second protein Disrupted-in- activated.42 In such a situation, it may be olfactory bulb, defects in secondary myo-
Schizophrenia1(DISC1)isfoundtobind efficient to have only one GEF present genesis.51 Trio was later demonstrated to
tothefirstpart,i.e.,theamino-half,ofthe with two distinct GEF domains that can interact with M-cadherin and to regulate
spectrin-repeatsofTrio.36Interestingly,by activate both GTPases in a spatially and myoblastfusionbymediatingRac1activa-
bindingofDISC1toTrio,theN-terminal temporallycoordinatedmanner.However, tion downstream of M-cadherin engage-
GEF domain is relieved from intramole- future experiments are needed to prove ment.58 These latter findings indicate that
cular inhibition and able to activate Rac1. such hypothesis. Trio may also be involved in regulating
Neubrand and colleagues showed that For Kalirin, it has been reported that cell-cell contacts.
Kidins220/ARMS binds to the spectrin- Kalirin7 localizes to postsynaptic densities
repeatsofTrio.21Theauthorsadditionally (PSD),43 where it is tyrosine phosphory- Trio and Cancer
showed that Kidins220/ARMS can also lated by EphB2 tyrosine kinasereceptor.44
bind to Kalirin. They hypothesized that Although the phosphorylation does not Seipel and coworkers have shown that the
Kidins220/ARMS mediates the cellular affect the GEF activity, it does change the N-terminal GEF domain of Trio induces
distribution of Trio in neuronal cells. distributionofKalirinandtherebychanges migration in 3T3 fibroblast cells and
As with the SEC14 domain, the its mode of action. The Rho-GEF Trio promotesanchorage-independentgrowth.4
relevance of the Trio spectrin-repeats is mayberegulatedinasimilarway.Debant Our recent data underscore these find-
still largely unclear, although the study of and colleagues indicated that Trio may be ings.16 Together with the knowledge that
Chen and coworkers suggest that the phosphorylated on serine and threonine Rac1 is involved in transformation and
repeats maybind tothe first GEF domain residues.1However,itisunclearifchanges tumor progression,60 these data suggest
and thereby preventing GTPase activa- inphosphorylationstatus ofTrio affect its that the ability of Trio to activate Rac1
tion.36 To fully understand its working distribution or activity. Another interest- and induce cell migration is linked to
mechanism, future studies are required. ing feature of Kalirin is its ability to bind tumor progression.
Trio and its two GEF domains. Trio specifically to iNOS, preventing dimeriza- Triowasfoundtobehighlyexpressedin
and its close relative Kalirin are unique in tion of iNOS, resulting in inhibition of glioblastoma,61 breast tumors,62,63 soft tis-
thattheycanactivatebothRac1andRhoA iNOS activity.45 This is an example of sue sarcomas64 and urinary bladder
with two separate GEF units within the Kalirin acting as a scaffold protein. The tumors.65 In addition, Trio levels are also
same molecule. Since overexpression of a group of Debant showed that Trio targets significantly increased in breast cancer
full-length Trio construct induces prim- Filamin in order to regulate the actin patients with poor predictive outcome.64
arily Rac1- and RhoG-dependent pheno- cytoskeleton.22 Thus, Rho-GEFs such as Moreover, Salhia and coworkers showed
typical changes,16,37 it is likely that the Trio and Kalirin cannot only act as that reduction of Trio using siRNA
activation of RhoA by the TrioD2 GEF proteins with enzymatic activity but may perturbed the migration capacity of glio-
domainistightlyregulatedwithintheTrio also be used by other proteins for correct blastomacellsinvitro.61Thesestudiesshow
molecule. Indeed, the PH-domain that is cellular targeting. that the expression of endogenous Trio is
adjacent to the TrioD2 DH-domain was increasedinseveraltypesofcancer,butdo
shown to negatively regulate RhoA activa- Trio and Neuronal Development notclarifyifTrioactivityisalsohampered.
tion.23 This auto-inhibition was shown to Tgat, an alternative splice variant
berelievedbybindingoftheGa -subunit Upon the finding that UNC-73, an encoding only the DH domain of the
q
of heterotrimeric G-proteins to a C- important regulator of axon guidance TrioD2 GEF unit of Trio, was identified
terminal extension of the PH-domain during nervous system development in in patients with adult T-cell leukemia and
resulting in RhoA activation.38,39 C. elegans, is an ortholog of mammalian was demonstrated to induce cell trans-
However, it remains unclear why Trio Trio,46 several studies followed dem- formation and tumor formation,15,66,67
expresses two catalytic GEF domains that onstratingaroleforTrioinaxonguidance indicating that also the C-terminal GEF
target small GTPases with apparent ant- and neuronal development in Drosophila domain of Trio may potentially regulate
agonistic downstream effects, i.e., RhoA and mammals.37,47-51 Trio was shown to cancer progression.
and Rac1. At this point one can only mediate Rac1 and/or RhoG activation Although Trio may potentially be an
speculate about their function. It is during neuronal growth cone migration interesting target in anti-tumor therapy, it
broadly accepted that Rho-GEFs deter- and axon guidance downstream of remains to be proven if increased protein
mine local activity of downstream several guidance receptors, including the levels or mutations indeed lead to changes
GTPases. Therefore, it may be that the Netrin receptor,52-54 Notch,55,56 SAX-3/ in Trio activity.
484 CellAdhesion&Migration Volume6Issue6
detectTrioinseveralleukemiccelllinesof
both myeloid and lymphoid origin, cor-
relatingTrioexpressionalsowithleukemic
cancers (Fig.2). Trio was also detected in
immature dendritic cells that were differ-
entiatedfromprimarymonocytes(Fig.2).
The expression of Trio in cell lines does
not prove that Trio is involved in
leukemia. However, it is an intriguing
hypothesis that Trio expression is
increased in these cell types and may
promotetheexchangerateonRac1,RhoG
Figure2.Trioexpressioninleukocytesandleukemiccelllines.Trio(350kDa)proteinexpressionin
and/or RhoA. Future studies will be
primaryperipheralbloodmononuclearcells(PBMC;lane1),naïvelymphocytes(lane2),neutrophils
required to show if Trio is a potential
(lane3)andmonocytes(lane4),followedbyHL60,HL60differentiatedtoneutrophil-likewith1.3%
(v/v)DMSO,U937cells,Jurkatandimmaturedendriticcells.Approximately100,000cellswere regulator of leukemic cell migration.
loadedperlane.Actin(40kDa)wasusedasacontrolforequalsampleloading.
Acknowledgments
We thank Dr. P.L. Hordijk for critically
Trio and Leukocytes leukocytes. Upon analysis of Trio expres- reading the manuscript. J.D. van B. is
sion in different types of leukocytes, we supportedbytheDutchHeartFoundation
Since Trio controls spreading and migra- were unable to detect endogenous, full- (grant no. 2005T039), LSBR fellowship
tion of HeLa cells, its role in these pro- length Trio protein in freshly isolated (fellowship no. 1028) and NWO Veni
cesses may potentially also be extrapolated neutrophils, monocytes and naïve lym- grant916.76.053.J.vanR.issupportedby
to other types of migratory cells, such as phocytes (Fig.2). Interestingly, we did AMCResearchB.V.
References 8. Saito K, Tautz L, Mustelin T. The lipid-binding 15. Yoshizuka N, Moriuchi R, Mori T, Yamada K,
SEC14 domain. Biochim Biophys Acta 2007; 1771: HasegawaS,MaedaT,etal.Analternativetranscript
1. DebantA,Serra-PagèsC,SeipelK,O’BrienS,Tang 719-26;PMID:17428729;http://dx.doi.org/10.1016/ derived from the trio locus encodes a guanosine
M,ParkSH,etal.ThemultidomainproteinTriobinds j.bbalip.2007.02.010 nucleotideexchangefactorwithmousecell-transform-
theLARtransmembranetyrosinephosphatase,contains 9. AlamMR,CaldwellBD,JohnsonRC,DarlingtonDN, ing potential. J Biol Chem 2004; 279:43998-4004;
aproteinkinasedomain,andhasseparaterac-specific Mains RE, Eipper BA. Novel proteins that interact PMID:15308664; http://dx.doi.org/10.1074/jbc.
and rho-specific guanine nucleotide exchange factor with the COOH-terminal cytosolic routing determi- M406082200
domains.ProcNatlAcadSciUSA1996;93:5466-71;
nants of an integral membrane peptide-processing 16. van Rijssel J, Hoogenboezem M, Wester L, Hordijk
PMID:8643598; http://dx.doi.org/10.1073/pnas.93.
enzyme. J Biol Chem 1996; 271:28636-40; PMID: PL,VanBuulJD.TheN-terminalDH-PHdomainof
11.5466
8910496;http://dx.doi.org/10.1074/jbc.271.45.28636 Trioinducescellspreadingandmigrationbyregulating
2. Bellanger JM, Lazaro JB, Diriong S, Fernandez A, 10. AlamMR,JohnsonRC,DarlingtonDN,HandTA, lamellipodia dynamics in a Rac1-dependent fashion.
Lamb N, Debant A. The two guanine nucleotide MainsRE,EipperBA.Kalirin,acytosolicproteinwith PLoSOne2012;7:e29912;PMID:22238672;http://
exchangefactordomainsofTriolinktheRac1andthe spectrin-like and GDP/GTP exchange factor-like dx.doi.org/10.1371/journal.pone.0029912
RhoApathwaysinvivo.Oncogene1998;16:147-52; domains that interacts with peptidylglycine alpha- 17. Abe K, Whitehead IP, O’Bryan JP, Der CJ.
PMID:9464532; http://dx.doi.org/10.1038/sj.onc.
amidating monooxygenase, an integral membrane Involvement of NH(2)-terminal sequences in the
1201532
peptide-processing enzyme. J Biol Chem 1997; 272: negativeregulationofVavsignalingandtransforming
3. BlangyA,VignalE,SchmidtS,DebantA,Gauthier- 12667-75;PMID:9139723;http://dx.doi.org/10.1074/ activity. J Biol Chem 1999; 274:30410-8; PMID:
Rouvière C, Fort P. TrioGEF1 controls Rac- and jbc.272.19.12667 10521418;http://dx.doi.org/10.1074/jbc.274.43.30410
Cdc42-dependent cell structures through the direct
11. ColomerV,EngelenderS,SharpAH,DuanK,Cooper 18. Vanderzalm PJ, Pandey A, Hurwitz ME, Bloom L,
activation of rhoG. J Cell Sci 2000; 113:729-39;
JK,LanahanA,etal.Huntingtin-associatedprotein1 Horvitz HR, Garriga G. C. elegans CARMIL
PMID:10652265
(HAP1)bindstoaTrio-likepolypeptide,witharac1 negatively regulates UNC-73/Trio function during
4. Seipel K, Medley QG, Kedersha NL, Zhang XA, guaninenucleotideexchangefactordomain.HumMol neuronal development. Development 2009; 136:
O’BrienSP,Serra-PagesC,etal.Trioamino-terminal Genet 1997; 6:1519-25; PMID:9285789; http://dx. 1201-10;PMID:19244282;http://dx.doi.org/10.1242/
guaninenucleotideexchangefactordomainexpression doi.org/10.1093/hmg/6.9.1519 dev.026666
promotesactincytoskeletonreorganization,cellmigra-
12. Portales-CasamarE,Briançon-MarjolletA,FromontS, 19. LeeCS,ChoiCK,ShinEY,SchwartzMA,KimEG.
tionandanchorage-independentcellgrowth.JCellSci
Triboulet R, Debant A. Identification of novel Myosin II directly binds and inhibits Dbl family
1999;112:1825-34;PMID:10341202
neuronal isoforms of the Rho-GEF Trio. Biol Cell guaninenucleotideexchangefactors:apossiblelinkto
5. MedleyQG,Serra-PagèsC,IannottiE,SeipelK,Tang 2006;98:183-93;PMID:16033331;http://dx.doi.org/ Rho family GTPases. J Cell Biol 2010; 190:663-74;
M, O’Brien SP, et al. The trio guanine nucleotide 10.1042/BC20050009 PMID:20713598; http://dx.doi.org/10.1083/jcb.
exchangefactorisaRhoAtarget.BindingofRhoAto 13. McPherson CE, Eipper BA, Mains RE. Genomic 201003057
the trio immunoglobulin-like domain. J Biol Chem
organization and differential expression of Kalirin 20. YanoT,YamazakiY,AdachiM,OkawaK,FortP,Uji
2000;275:36116-23;PMID:10948190;http://dx.doi.
isoforms. Gene 2002; 284:41-51; PMID:11891045; M,etal.Taraup-regulatesE-cadherintranscriptionby
org/10.1074/jbc.M003775200
http://dx.doi.org/10.1016/S0378-1119(02)00386-4 binding to the Trio RhoGEF and inhibiting Rac
6. MedleyQG,BuchbinderEG,TachibanaK,NgoH, 14. SunYJ,NishikawaK,YudaH,WangYL,OsakaH, signaling. J Cell Biol 2011; 193:319-32; PMID:
Serra-Pagès C, Streuli M. Signaling between focal FukazawaN,etal.Solo/Trio8,amembrane-associated 21482718;http://dx.doi.org/10.1083/jcb.201009100
adhesion kinase and trio. J Biol Chem 2003; 278:
shortisoformofTrio,modulatesendosomedynamics
13265-70; PMID:12551902; http://dx.doi.org/10.
andneuriteelongation.MolCellBiol2006;26:6923-
1074/jbc.M300277200
35; PMID:16943433; http://dx.doi.org/10.1128/
7. McPhersonCE,EipperBA,MainsRE.Multiplenovel MCB.02474-05
isoforms of Trio are expressed in the developing rat
brain. Gene 2005; 347:125-35; PMID:15715966;
http://dx.doi.org/10.1016/j.gene.2004.12.028
www.landesbioscience.com CellAdhesion&Migration 485
21. Neubrand VE, Thomas C, Schmidt S, Debant A, 35. Alam MR, Steveson TC, Johnson RC, Bäck N, 49. LieblEC,ForsthoefelDJ,FrancoLS,SampleSH,Hess
SchiavoG.Kidins220/ARMSregulates Rac1-depend- Abraham B, Mains RE, et al. Signaling mediated by JE,CowgerJA,etal.Dosage-sensitive,reciprocalgenetic
ent neurite outgrowth by direct interaction with the thecytosolicdomainofpeptidylglycinealpha-amidat- interactions between the Abl tyrosine kinase and the
RhoGEFTrio.JCellSci2010;123:2111-23;PMID: ingmonooxygenase.MolBiolCell2001;12:629-44; putativeGEFtriorevealtrio’sroleinaxonpathfinding.
20519585;http://dx.doi.org/10.1242/jcs.064055 PMID:11251076 Neuron2000;26:107-18;PMID:10798396;http://dx.
22. BellangerJM,AstierC,SardetC,OhtaY,StosselTP, 36. Chen SY, Huang PH, Cheng HJ. Disrupted-in- doi.org/10.1016/S0896-6273(00)81142-3
DebantA.TheRac1-andRhoG-specificGEFdomain Schizophrenia 1-mediated axon guidance involves 50. NewsomeTP,SchmidtS,DietzlG,KelemanK,Asling
of Trio targets filamin to remodel cytoskeletal actin. TRIO-RAC-PAK small GTPase pathway signaling. B,DebantA,etal.Triocombineswithdocktoregulate
Nat Cell Biol 2000; 2:888-92; PMID:11146652; ProcNatlAcadSciUSA2011;108:5861-6;PMID: Pakactivityduringphotoreceptoraxonpathfindingin
http://dx.doi.org/10.1038/35046533 21422296;http://dx.doi.org/10.1073/pnas.1018128108 Drosophila.Cell2000;101:283-94;PMID:10847683;
23. Bellanger JM, Estrach S, Schmidt S, Briançon- 37. EstrachS,SchmidtS,DiriongS,PennaA,BlangyA, http://dx.doi.org/10.1016/S0092-8674(00)80838-7
Marjollet A, Zugasti O, Fromont S, et al. Different FortP,etal.TheHumanRho-GEFtrioanditstarget 51. O’BrienSP,SeipelK,MedleyQG,BronsonR,Segal
regulationoftheTrioDbl-Homologydomainsbytheir GTPase RhoG are involved in the NGF pathway, R,StreuliM.Skeletalmuscledeformityandneuronal
associated PH domains. Biol Cell 2003; 95:625-34; leadingtoneuriteoutgrowth.CurrBiol2002;12:307-12; disorder in Trio exchange factor-deficient mouse
PMID:14720465; http://dx.doi.org/10.1016/j.biolcel. PMID:11864571; http://dx.doi.org/10.1016/S0960- embryos.ProcNatlAcadSciUSA2000;97:12074-
2003.10.002 9822(02)00658-9 8; PMID:11050238; http://dx.doi.org/10.1073/pnas.
24. OhtaY,SuzukiN,NakamuraS,HartwigJH,Stossel 38. RojasRJ,YoheME,GershburgS,KawanoT,Kozasa 97.22.12074
TP.ThesmallGTPaseRalAtargetsfilamintoinduce T, Sondek J. Galphaq directly activates p63RhoGEF 52. ForsthoefelDJ,LieblEC,KolodziejPA,SeegerMA.
filopodia.ProcNatlAcadSciUSA1999;96:2122-8; and Trio via a conserved extension of the Dbl The Abelson tyrosine kinase, the Trio GEF and
PMID:10051605; http://dx.doi.org/10.1073/pnas.96. homology-associated pleckstrin homology domain. J EnabledinteractwiththeNetrinreceptorFrazzledin
5.2122 Biol Chem 2007; 282:29201-10; PMID:17606614; Drosophila.Development2005;132:1983-94;PMID:
25. JeonYJ,ChoiJS,LeeJY,YuKR,KaSH,ChoY,etal. http://dx.doi.org/10.1074/jbc.M703458200 15790972;http://dx.doi.org/10.1242/dev.01736
Filamin B serves as a molecular scaffold for type I 39. WilliamsSL,LutzS,CharlieNK,VettelC,AilionM, 53. Briançon-MarjolletA,GhoghaA,NawabiH,TrikiI,
interferon-inducedc-JunNH2-terminalkinasesignal- CocoC,etal.Trio’sRho-specificGEFdomainisthe Auziol C, Fromont S, et al. Trio mediates netrin-1-
ingpathway.MolBiolCell2008;19:5116-30;PMID: missing Galpha q effector in C. elegans. Genes Dev induced Rac1 activation in axon outgrowth and
18815275;http://dx.doi.org/10.1091/mbc.E08-06-0576 2007; 21:2731-46; PMID:17942708; http://dx.doi. guidance. Mol Cell Biol 2008; 28:2314-23; PMID:
26. Del Valle-Pérez B, Martínez VG, Lacasa-Salavert C, org/10.1101/gad.1592007 18212043;http://dx.doi.org/10.1128/MCB.00998-07
FiguerasA,ShapiroSS,TakafutaT,etal.FilaminB 40. KraynovVS,ChamberlainC,BokochGM,Schwartz 54. PengYJ,HeWQ,TangJ,TaoT,ChenC,GaoYQ,
playsakeyroleinvascularendothelialgrowthfactor- MA,SlabaughS,HahnKM.LocalizedRacactivation etal.Trioisakeyguaninenucleotideexchangefactor
inducedendothelialcellmotilitythroughitsinteraction dynamicsvisualizedinlivingcells.Science2000;290: coordinatingregulationofthemigrationandmorpho-
withRac-1andVav-2.JBiolChem2010;285:10748- 333-7; PMID:11030651; http://dx.doi.org/10.1126/ genesisofgranulecellsinthedevelopingcerebellum.J
60; PMID:20110358; http://dx.doi.org/10.1074/jbc. science.290.5490.333 Biol Chem 2010; 285:24834-44; PMID:20516067;
M109.062984 41. Pertz O, Hodgson L, Klemke RL, Hahn KM. http://dx.doi.org/10.1074/jbc.M109.096537
27. Rossman KL, Der CJ, Sondek J. GEF means go: SpatiotemporaldynamicsofRhoAactivityinmigrating 55. Le Gall M, De Mattei C, Giniger E. Molecular
turning on RHO GTPases with guanine nucleotide- cells. Nature 2006; 440:1069-72; PMID:16547516; separationoftwosignalingpathwaysforthereceptor,
exchangefactors.NatRevMolCellBiol2005;6:167- http://dx.doi.org/10.1038/nature04665 Notch.DevBiol2008;313:556-67;PMID:18062953;
80; PMID:15688002; http://dx.doi.org/10.1038/ 42. WelchCM,ElliottH,DanuserG,HahnKM.Imaging http://dx.doi.org/10.1016/j.ydbio.2007.10.030
nrm1587 the coordination of multiple signalling activities in 56. SongJK,GinigerE.NoncanonicalNotchfunctionin
28. Aravind L, Neuwald AF, Ponting CP. Sec14p-like livingcells.NatRevMolCellBiol2011;12:749-56; motoraxonguidanceismediatedbyRacGTPaseand
domainsinNF1 and Dbl-like proteinsindicate lipid PMID:22016058;http://dx.doi.org/10.1038/nrm3212 theGEF1domainofTrio.DevDyn2011;240:324-
regulationofRasandRhosignaling.CurrBiol1999;9: 43. RabinerCA,MainsRE,EipperBA.Kalirin:adualRho 32;PMID:21246649;http://dx.doi.org/10.1002/dvdy.
R195-7;PMID:10209105;http://dx.doi.org/10.1016/ guanine nucleotide exchange factor that is so much 22525
S0960-9822(99)80127-4 morethanthesumofitsmanyparts.Neuroscientist 57. Watari-GoshimaN,OguraK,WolfFW,GoshimaY,
29. Bankaitis VA, Mousley CJ, Schaaf G. The Sec14 2005;11:148-60;PMID:15746383;http://dx.doi.org/ GarrigaG.C.elegansVAB-8andUNC-73regulatethe
superfamilyandmechanismsforcrosstalkbetweenlipid 10.1177/1073858404271250 SAX-3receptortodirectcellandgrowth-conemigra-
metabolism and lipid signaling. Trends Biochem Sci 44. PenzesP,BeeserA,ChernoffJ,SchillerMR,Eipper tions. Nat Neurosci 2007; 10:169-76; PMID:
2010;35:150-60;PMID:19926291;http://dx.doi.org/ BA,MainsRE,etal.Rapidinductionofdendriticspine 17237778;http://dx.doi.org/10.1038/nn1834
10.1016/j.tibs.2009.10.008 morphogenesisbytrans-synapticephrinB-EphBrecep- 58. CharrasseS,ComunaleF,FortierM,Portales-Casamar
30. Mousley CJ, Tyeryar KR, Vincent-PopeP, Bankaitis toractivationoftheRho-GEFkalirin.Neuron2003; E, Debant A, Gauthier-Rouvière C. M-cadherin
VA.TheSec14-superfamilyandtheregulatoryinterface 37:263-74; PMID:12546821; http://dx.doi.org/10. activates Rac1 GTPase through the Rho-GEF trio
between phospholipid metabolism and membrane 1016/S0896-6273(02)01168-6 duringmyoblastfusion.MolBiolCell2007;18:1734-
trafficking. Biochim Biophys Acta 2007; 1771:727- 45. RatovitskiEA,AlamMR,QuickRA,McMillanA,Bao 43;PMID:17332503;http://dx.doi.org/10.1091/mbc.
36; PMID:17512778; http://dx.doi.org/10.1016/j. C,KozlovskyC,etal.Kalirininhibitionofinducible E06-08-0766
bbalip.2007.04.002 nitric-oxidesynthase.JBiolChem1999; 274:993-9; 59. BouquierN,VignalE,CharrasseS,WeillM,Schmidt
31. KostenkoEV,MahonGM,ChengL,WhiteheadIP. PMID:9873042; http://dx.doi.org/10.1074/jbc.274.2. S, Léonetti JP, et al. A cell active chemical GEF
The Sec14 homology domain regulates the cellular 993 inhibitor selectively targets the Trio/RhoG/Rac1 sig-
distribution and transforming activity of the Rho- 46. Steven R, Kubiseski TJ, Zheng H, Kulkarni S, nalingpathway.ChemBiol2009;16:657-66;PMID:
specificguaninenucleotideexchangefactorDbs.JBiol MancillasJ,RuizMoralesA,etal.UNC-73activates 19549603; http://dx.doi.org/10.1016/j.chembiol.
Chem 2005; 280:2807-17; PMID:15531584; http:// the Rac GTPase and is required for cell and growth 2009.04.012
dx.doi.org/10.1074/jbc.M411139200 conemigrationsinC.elegans.Cell1998;92:785-95; 60. JaffeAB,HallA.RhoGTPasesintransformationand
32. Djinovic-CarugoK,GautelM,YlänneJ,YoungP.The PMID:9529254; http://dx.doi.org/10.1016/S0092- metastasis. Adv Cancer Res 2002; 84:57-80; PMID:
spectrin repeat: a structural platform for cytoskeletal 8674(00)81406-3 11883532; http://dx.doi.org/10.1016/S0065-230X
protein assemblies. FEBS Lett 2002; 513:119-23; 47. AwasakiT,SaitoM,SoneM,SuzukiE,SakaiR,ItoK, (02)84003-9
PMID:11911890; http://dx.doi.org/10.1016/S0014- et al. The Drosophila trio plays an essential role in 61. SalhiaB,TranNL,ChanA,WolfA,NakadaM,Rutka
5793(01)03304-X patterning of axons by regulating their directional F,etal.Theguaninenucleotideexchangefactorstrio,
33. XinX,FerraroF,BäckN,EipperBA,MainsRE.Cdk5 extension.Neuron2000;26:119-31;PMID:10798397; Ect2, and Vav3 mediate the invasive behavior of
andTriomodulateendocrinecellexocytosis.JCellSci http://dx.doi.org/10.1016/S0896-6273(00)81143-5 glioblastoma.AmJPathol2008;173:1828-38;PMID:
2004; 117:4739-48; PMID:15331630; http://dx.doi. 48. Bateman J, Shu H, Van Vactor D. The guanine 19008376; http://dx.doi.org/10.2353/ajpath.2008.
org/10.1242/jcs.01333 nucleotide exchange factor trio mediates axonal 080043
34. CiccotostoGD,SchillerMR,EipperBA,MainsRE. development in the Drosophila embryo. Neuron
Induction of integral membrane PAM expression in 2000; 26:93-106; PMID:10798395; http://dx.doi.
AtT-20cellsaltersthestorageandtraffickingofPOMC org/10.1016/S0896-6273(00)81141-1
and PC1. J Cell Biol 1999; 144:459-71; PMID:
9971741;http://dx.doi.org/10.1083/jcb.144.3.459
486 CellAdhesion&Migration Volume6Issue6
62. Lane J, Martin TA, Mansel RE, Jiang WG. The 64. AdamowiczM,RadlwimmerB,RiekerRJ,MertensD, 66. YamadaK,MoriuchiR,MoriT,OkazakiE,KohnoT,
expression and prognostic value of the guanine SchwarzbachM,SchramlP,etal.Frequentamplifica- Nagayasu T, et al. Tgat, a Rho-specific guanine
nucleotide exchange factors (GEFs) Trio, Vav1 and tionsandabundantexpressionofTRIO,NKD2,and nucleotide exchange factor, activates NF-kappaB via
TIAM-1 in human breast cancer. Int Semin Surg IRX2 in soft tissue sarcomas. Genes Chromosomes physical association with IkappaB kinase complexes.
Oncol 2008; 5:23; PMID:18925966; http://dx.doi. Cancer2006;45:829-38;PMID:16752383;http://dx. Biochem Biophys Res Commun 2007; 355:269-74;
org/10.1186/1477-7800-5-23 doi.org/10.1002/gcc.20343 PMID:17292329; http://dx.doi.org/10.1016/j.bbrc.
63. SosaMS,Lopez-HaberC,YangC,WangH,Lemmon 65. ZhengM,SimonR,MirlacherM,MaurerR,GasserT, 2007.01.147
MA,BusilloJM,etal.IdentificationoftheRac-GEFP- ForsterT,etal.TRIOamplificationandabundantmRNA 67. BouquierN,FromontS,ZeehJC,AuziolC,Larrousse
Rex1 as an essential mediator of ErbB signaling in expressionisassociatedwithinvasivetumorgrowthand P,RobertB,etal.Aptamer-derivedpeptidesaspotent
breast cancer. Mol Cell 2010; 40:877-92; PMID: rapidtumorcellproliferationinurinarybladdercancer. inhibitorsoftheoncogenicRhoGEFTgat.ChemBiol
21172654; http://dx.doi.org/10.1016/j.molcel.2010. AmJPathol2004;165:63-9;PMID:15215162;http:// 2009; 16:391-400; PMID:19389625; http://dx.doi.
11.029 dx.doi.org/10.1016/S0002-9440(10)63275-0 org/10.1016/j.chembiol.2009.02.006
www.landesbioscience.com CellAdhesion&Migration 487