Journal of Cell Science 1 dysplasia Genot faciogenital Elisabeth matrix from extracellular lessons of – regulator remodelling central a as FGD1 Hypothesis hnrctsadotolss oepeiey G1i not detected is is but skeletogenesis, FGD1 of is phases precisely, earlier More the FGD1 in osteoblasts. expressed proliferating skeleton, periostium, and the mouse and chondrocytes perichondrium mesenchymal 2000). developing for pre-cartilaginous the al., in condensations, the clues expressed et exclusively within important (Gorski almost provided fact, pathogenesis FGDY has In of embryos FGD1 understanding of mouse pattern expression spatiotemporal in the Hall, of and study (Schmidt A GTPases Rho 2002). the (GEFs) of factors activation exchange the nucleotide regulate guanine that of family DBL the of Scriver 1994; al., et 2001). Pasteris al., 2010; urogenital retardation al., et et mental anomalies, Orrico mild 2002; cases, al., skeletal et of short (Lebel number by a disproportionately in accompanied a and, malformations is appearance, that facial result FGDY stature dysmorphic which with features, a Patients craniofacial 2001). of in al., set distinguishing et a Scriver present the 1994; al., cause et 305400)] 1), dysplasia (Pasteris (OMIM Fig. syndrome Aarskog-Scott faciogenital as (Xp11.21, known disorder also chromosome [FGDY, developmental X X-linked the human of arm short the in Mutations Introduction dysplasia. faciogenital diseases, of complex and pathogenesis physiology the us in of words: help (ECM) understanding Key might matrix FGD1 possibly extracellular our of the and furthering biology and of remodelling time, we cell remodelling invadopodia matrix the same Here, with studying extracellular of signalling the cells. how CDC42 controlling function at endothelial on link events and focus while, and that of we tumour dots formation Additionally, regulator the in settings. the important connect unveiled matrix pathological to of an studies and extracellular be physiological regulation recent the in might Two the of invasion FGD1 development. degradation cell in that bone to involvement hypothesis of devoted its the regulation structures as the discuss particular, well FGD1 cellular in as in which are disease, involved FGD1, by which the is of podosomes, of mechanisms protein pathology cellular the functions the but that The potential unclear, show transformation. remain new dysplasia clearly tumorigenic secretory faciogenital discoveries, of and of activation, recent deformations number cycle skeletal transcriptional some a cell hallmark rearrangements, the in the to membrane and during lead cytoskeleton-dependent mutations transition anomalies, controls G1 urogenital CDC42 trafficking, and (CDC42). membrane skeletal 42 facial, cycle stature, division short retardation. disproportionately mental in mild cases, results that disorder the developmental in mutations Disabling Summary 10.1242/jcs.093419 doi: 3265–3270 125, ß Science Cell of Journal 2012 March 27 Accepted ( correspondence for *Author 6 5 4 3 2 uorCl nainLbrtr,CnozoMroNgiSd .MraIbr,Cit 63,Italy 66030, Chieti Imbaro, Maria S. Italy Sud, 53100, Negri Siena Mario Siena, Consorzio of Laboratory, University Invasion France Section, Cell Pessac, Medicine Tumour 33607 Molecular Escarpit, Neurosciences, France Robert of Bordeaux, rue Department F-33076 2 France Bordeaux, Biology, Bordeaux, de and F-33000 CHU Chemistry U1053, of Foie, Institute du European Cancer du Physiopathologie INSERM, Universite 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. The FGD1 eBreu,Pyiptooi uCne uFi,U03 -30 odax France Bordeaux, F-33000 U1053, Foie, du Cancer du Physiopathologie Bordeaux, de ´ aso-ct ydoe C eoeln,Fcoeia ypai,FD,Ivdpda Podosomes Invadopodia, FGD1, dysplasia, Faciogenital remodelling, ECM syndrome, Aarskog-Scott eeecdsteFD rti,wihi member a is which protein, FGD1 the encodes gene FGD1 1,2,3,4 [email protected] ee hc slclzdt h proximal the to localized is which gene, hmsDaubon Thomas , FGD1 FGD1 eecuefcoeia ypai as nw sArkgSotsnrm) ua X-linked human a syndrome), Aarskog-Scott as known (also dysplasia faciogenital cause gene ) noe h unn uloieecag atrFD,wihi pcfcfrteRoGPs cell GTPase Rho the for specific is which FGD1, factor exchange nucleotide guanine the encodes 1,2,3 icnoSorrentino Vincenzo , E ntecnrlo xrclua arx(C)remodelling (ECM) this matrix for extracellular roles of potential control with unveiling twist the by new in function a GEF 1996). FGD1 introduced al., have to et studies regards (Olson recent cytoskeleton- transformation two tumorigenic However, controls and the cycle FGD1 during cell G1 through 2), transition activation, membrane-trafficking, (Fig. GTPase transcriptional secretory rearrangements, to (CDC42) membrane leads dependent 42 that division GTPases, cell GTPase switch cycle the Rho the on molecular activating specifically GTP By activation. a for GDP activating of transformation. thereby exchange oncogenic the and catalyze adhesion GEFs cell cell transcription, cell progression, gene shape, cytokinesis), cycle cell and the to movement cell changes of polarity, bone affecting reorganisation (thereby including of cytoskeleton processes, actin regulator biological skeletal important of the variety an is of least, most very that with the development. suggests which consistent skeletal at patients, FGD1, FGDY is the in observed FGD1 expressionmalformations phalanges, the of and Therefore, periaxial 2000). and al., pattern the bones, et and (Gorski crest, craniofacial bones mesoderm neural lateral the of long from derived components components ribs, skeletal ossifying vertebrae, the in h Tae neatwt hi fetrpoen odiealarge a drive to proteins effector their with interact GTPases Rho 5 n oet Buccione Roberto and 6, * 3265 Journal of Cell Science on)ada cie(T-on)fr.Teecag fGDP of exchange The (GDP- form. inactive (GTP-bound) an active between an shape, cycle and bound) GTPases and cell Rho Ellenbroek 2005; 2007). Hall, as Collard, 2002; dissemination Hall, such and metastatic fundamental (Etienne-Manneville and events, actin affect motility and polarization, pathological thereby, morphology, Ellenbroek kinases, and GTPases, 2005; protein These physiological (Hall, 2007). including phospholipases Collard, and targets, stimulating, low nucleators that and effector of with, switches interacting family molecular by various Rho functions are the cell They many of control GTPases. members are weight CDC42 molecular FGD1 and of biology Rac cell Rho, the to and FGDY between physiology From in connections remodelling the ECM of diseases. and complex function of understanding its signalling regulation of our the CDC42 investigation in further that hub and will signalling events a remodelling is ECM the FGD1 present that will we in hypothesis Finally, by involved components. diseases, trait are shared multifactorial the that highlighting common pathways of and the processes reconstruct understanding are physiological to but our us pathogenesis, FGDY helping further and also FGD1 and only function of CDC42 not studies of remodelling) biological complexity interactors cell how its bone regulated discuss and events will disease) We and FGD1. vascular by and cancer vascular (e.g. physiological pathological the development, of provided understanding unexpectedly (e.g. our has towards clues disorder important Mendelian rare extremely Daubon cancer 2009; during al., et namely 2011). 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GTPase the the dissociation These the and nucleotide classes; cycle. guanine (GDIs) main this the inhibitors three of (GAPs), of proteins regulation part activating proper are proteins the accessory ensure accessory to require thus, proteins and and activity, hydrolytic GTP exchange limited bound have nucleotide GTPases of guanine small hydrolysis the by However, GDP. terminated interaction to is allows which that effectors, change conformational with a induces GTP for hsrset si osntdrc h oaiaino G1t such FGD1 to the because FGD1 be of might localization This in 2001). the al., atypical direct et be (Estrada not membranes does to 2007). it appears al., as however, et respect, FGD1, this (Hayakawa of system domain endosomal FYVE the The of those as PtdIns(3) such to proteins domain-containing phosphatidyl-inositol-3-phosphate with this to bind [PtdIns(3) serve specificity usually and domains to 2002), affinity FYVE seem 2001). high not Hall, al., does et and domain (Estrada function PH (Schmidt C-terminal the location whereas the 2001). intracellular to FGD1 al., of targeting appropriate et the help (Estrada could domain activity PH the N-terminal The exchange and nucleotide involving guanine cytoskeleton regulates negatively the interactions N-terminus actin the addition, protein–protein subcortical In thought tracts. polyproline through the is region complex to N-terminal Golgi recruited FGD1 be The 2001). to or time al., this cytoskeletal et at other excluded (Estrada be to cannot ligands FGD1 protein of transduction al., signal binding et the (Hou DBNL) Obviously, as 2003). known mammalian also and (mAbp1, cortactin protein two actin-binding are however, only interactors, The FGD1 3 profilin. known as homology and known Src also proteins for (EVH1, SPRE1)-domain-containing 1 sites Ena/VASP-homology binding and potential WW- (SH3)-, has al., et PRD Pasteris 2000; The al., 1994). et (Gorski domain and PH domain, C-terminal (FYVE) also second EEA1 a FGD1 and Vps27 1). cysteine-rich YOTB, Fab-1, a (Fig. zinc-finger (PRD), GTP domain proline-rich for N-terminal an GDP features CDC42-bound the of catalyze domains exchange pleckstrin two a these Together, to domain. adjacent (PH) DBL positioned homology a is contains that FGD1 domain GEFs, (DH) Rho homology most Like CDC42. for specific are GEFs how and spatial understood regulators. as candidates Rho-GTPase poorly powerful temporal represent still clearly metastatic is they increased regulated, it and/or Although invasiveness and growth, potential. can invasion GEF aberrant of in expression to deregulated lead involved as 2010), al., components et (Vigil important instance, metastasis For be 1998). al., might et (Zhou GEFs systems cell and functions cellular bratsgaln hog h Tae a fe been often has GTPases Rho through signalling Aberrant n uhGFi G1 hc osse E ciiyta is that activity GEF a possesses which FGD1, is GEF such One P ,adti neato scuilfrtreigFYVE- targeting for crucial is interaction this and ], P erce membranes, -enriched Journal of Cell Science R1Q,sm aeas endsrbdi h R (S205I, domain PRD the PH in adjacent described the been R443H, catalytic also and or the have S558W) R443L 1). some in (Fig. and R442H, (R610Q), located point R522H R408Q, domains are missense R402Q, M466V, functional mutations (E380A, (3) point the region or most mutations within proteins; frameshift Whereas entire located and the FGD1 of nonsense mutations deletion truncated (2) (1) frame; yielding patients: FGDY coding in FDG1 of found types this been three In that FGDY. have interest disease of X-linked is the it causes context, gene, its in Kutateladze, mutations 2001; al., et (Sankaran ring 6-hydroxyl and inositol 2006). 5- 4-, the the of of WxxD recognition groups the the fact, for important In is specificities. 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Hall, R. Buccione, and F. Attanasio, I., Ayala, G., Caldieri, NSGR[rn ubr22 oEG] ..i h eiin fa of recipient the is T.D. fellowship. E.G.]. Association Research to Cancer 2823 France number [grant GDR CNRS abn . ucoe .adGe and R. Buccione, T., Daubon, Maı E., Reuzeau, C., Varon, F., Tatin, P., Mariggio Rottiers, C., Billottet, F., Attanasio, G., Caldieri, G., Giacchetti, I., Ayala, osi .L,Etaa . u .adLu Z. Liu, and C. Hu, L., Estrada, L., J. Gorski, a,L,Grk,J .adCe,C S. C. Chen, and L. J. Gorski, L., Gao, A. Hall, and S. Etienne-Manneville, L. J. Gorski, and E. Caron, L., Estrada, G. J. Collard, and I. S. Ellenbroek, V., M. A. Egorova, A., Gunel, Pentima, Di and A., O. H. Vorontsova, M., M. Capestrano, V., Johnson, M. Egorov, M., N. Amankulor, L., M. DiLuna, Franklin, R., J. Delatore, Jr, C., W. Calton, M., J. Johanning, J., P. S. Armstrong, J. Beckmann, and E. S. Antonarakis, References Agency n Cancer Research ARC France number National the E.G.], [grant French to Association 01 number the 1237 Research BLAN Italian R.B.], [grant 2010 ANR and number the Programme [grant E.G. by Framework to supported Seventh 237946 the was Union the R.B.), to laboratories European Italy Milano, (AIRC, authors’ Research Cancer for the Association in Work Funding artwork. the for Fontana Elena thank obtained We findings of Acknowledgements result disorders. inherited a biological of study as the cell diseases through to and pathway of complex physiology, novel to extended and common, and power created monitored and be be can the can components normal hypotheses Through reconstruct new our approaches, to 2006). and improve (Antonarakis us previously Beckmann, substantially discussed helping as to pathways, common, by pathological of potential basis diseases function, functional the protein and complex molecular and with the gene of into as understanding of gold view knowledge well virtual unique our as further a represent the to us disorders from mines afford Mendelian away that taken pathophysiology. knockouts’ spontaneous be with allelic us can ‘human provide diseases lesson monogenic that important knowledge an However, 3270 aaaa . ae,S,Load . abih,D n ovr,S. Corvera, and D. Lambright, D., Leonard, S., Hayes, A., Hayakawa, 33 g1drn oefrainadseea eet nfcoeia ypai (FGDY; dysplasia faciogenital in defects skeletal and syndrome). formation Aarskog bone during Fgd1 invadopodia. of biology Ge formation. and V. Moreau, atrFD euae segnssi ua eecya tmcells. stem mesenchymal human 178 in osteogenesis regulates FGD1 factor 629-635. subcortical the to membrane. localized Golgi is and dysplasia, cytoskeleton faciogenital actin for responsible factor exchange the from cancer. with proteins cargo of activation. Cdc42 export via regulates complex (FGD1) golgi protein dysplasia Faciogenital Mariggio syndrome. Aarskog-Scott with 49 associated in disease remodeling Cerebrovascular matrix extracellular and 31 factor formation growth podosome transforming regulates Fgd1 cancer. breast degradation and matrix prostate extracellular in and up-regulated biogenesis is R. and invadopodia Buccione, regulates and Fgd1 V. R. protein Castronovo, J. R., Elmore, Polishchuk, and disease. J. occlusive D. versus aneurysmal Carey, aorta: Surg. abdominal C., human D. in expression Han, P., D. attention. vltoaiycnevdsrcua n ucinlrlso h YEdomain. FYVE the of roles functional and Symp. Soc. structural Biochem. conserved Evolutionarily 457-461. , 4430-4441. , 891-895. , 969-974. , 35 20) h Tae n h oto fcl behaviour. cell of control the and GTPases Rho (2005). 346-355. , ,S,Aaa .I,Tete I., M. Ayala, S., `, a.Rv Genet. Rev. Nat. ora fCl cec 2 (14) 125 Science Cell of Journal u.J elBiol. Cell J. Eur. ln x.Metastasis Exp. Clin. nt E. ´not, e.Dyn. Dev. 74 95-105. , n.Rv elMl Biol. Mol. Cell Rev. Int. 7 277-282. , b 87 20) euaoysgasfredteilpodosome endothelial for signals Regulatory (2008). siuae otcedteilcells. endothelial aortic -stimulated nt E. ´not, 543-554. , 218 20) h Tae ncl biology. cell in GTPases Rho (2002). ,S,Grk,J . un,A tal. et A. Luini, L., J. Gorski, S., `, 24 573-586. , 20) h Tae:fntosadassociation and functions GTPases: Rho (2007). 21) h d4 unn uloieexchange nucleotide guanine Cdc42 The (2011). o.Bo.Cell Biol. Mol. 657-672. , 21) h aso-ct ydoeprotein syndrome Aarskog-Scott The (2011). 20) g1 h d4 unn nucleotide guanine Cdc42 the Fgd1, (2001). 20) edla iodr eev more deserve disorders Mendelian (2006). u.Ml Genet. Mol. Hum. 20) kltlseii xrsinof expression Skeletal-specific (2000). 275 acrRes. Cancer 20 1-34. , 20) aigntldysplasia Faciogenital (2009). ˚ 2413-2427. , 00t .. n the and E.G.) to 5040 20) eladmolecular and Cell (2009). 20) ifrnilgene Differential (2002). 10 485-495. , ice.Sc Trans. Soc. Biochem. 69 te .L,Sle,F., Saltel, L., J. ˆtre, 747-752. , ,S,Tete S., `, o.Cl.Biol. Cell. Mol. Neuroradiology m .Pathol. J. Am. Nature .Vasc. J. (2009). (2007). (2007). ,S., `, 420 , o,W,Genlt,M . hm .H,Kn,S,Za,B,Ltnn . rd,N,Hu, N., Brady, S., Lotinun, B., Zhai, S., Kant, H., J. Shim, B., M. Greenblatt, W., Zou, hu . ag . osi .L,Nmr,N,Clad .adBkc,G M. G. Bokoch, and J. Collard, N., Nomura, L., J. Gorski, Y., Wang, K., Zhou, E. Y. Zhang, sia . uio . no .adHykw,M. Hayakawa, and K. Ando, T., Fujino, T., Oshima, Hertz, M., S. Azzarello-Burri, J., Clayton-Smith, L., Faivre, L., Galli, A., Orrico, htha,I . b,K,Grk,J .adDr .J. C. Der, and L. J. Gorski, K., Abe, P., I. Whitehead, C., Billottet, V., Tridon, B., Chaigne-Delalande, T., Daubon, F., Saltel, P., Rottiers, aaa . resn,M,Lmrh,N,Grk,J .adHl,A. A. Hall, Hall, and L. and J. Gorski, L. G., N. Pasteris, J. F., M. Gorski, Olson, N., Lamarche, M., Driessens, K., Nagata, adl,E,Guas .J n e ik,P. Dijke, ten and J. M. Goumans, E., Z. Pardali, Werb, and J. A. Ewald, A., Page-McCaw, S. Linder, and G. Zenner, E., A. Osiak, M. Hayakawa, and K. Ando, T., Fujino, T., Oshima, ag . i-uel,H,Hri,O,Bni,P,Rmhlwn . ae,S., Taleb, B., Ramkhelawon, P., Bonnin, O., Herbin, H., Ait-Oufella, Y., Wang, A. M. Lemmon, and M. M. Sachdeva, E., D. Klein, G., V. Sankaran, Stevenson, E., C. Schwartz, E., M. Porteous, J., L. Logie, A., Cadle, G., N. Pasteris, idr . ise,C n iml M. Himmel, and C. Wiesner, S., Linder, A. J. Cooper, and L. J. Gorski, P., Hou, K., Kim, S. J. Ikonomidis, and G. F. Spinale, L. A., J. J. Jones, Gorski, and B. A. Vojtek, T., J. Parsons, W., A. Kinley, L., Estrada, K. P., Hou, Kikugawa, and M. Kitagawa, K., Miyazawa, H., Kitagawa, M., Hayakawa, ii,D,Cefl,J,Rsmn .L n e,C J. C. Der, and L. K. Rossman, J., Cherfils, D., Vigil, and W. K. Kinzler, B., Childs, D., Valle, S., W. Sly, L., A. Beaudet, R., C. A. Scriver, Hall, and A. Schmidt, ee,R . a,M,Pus . us .A,Seesn .E n cwrz .E. C. Schwartz, and E. R. Stevenson, A., H. Lubs, S., Pouls, M., May, R., R. Lebel, G. T. Kutateladze, ea .M n ily .J. A. Ridley, and M. F. Vega, S., Fernandez-Sauze, E., Obberghen-Schilling, Van V., Moreau, F., Tatin, C., Varon, ontemo h aigntldslsapoenFD nmice. in FGD1 4392. protein dysplasia faciogenital the of downstream D.Z.,Gygi,S.P.,Baron,R.etal. 19) unn uloieecag atr euaeseiiiyo downstream of specificity regulate Cdc42. factors and Rac exchange from signaling nucleotide Guanine (1998). .M,Jcumn,S,Tuiao . rooCrea . aatn,E tal. mutations et novel E. nine Tarantino, of gene. I., report FGD1 Carrera, and the update Arroyo of clinical R., syndrome: Taurisano, Aarskog-Scott S., (2010). Jacquemont, M., J. as itntsgaigadtasomn activities. transforming and signaling distinct cause vessels. arterial in degradation collagen membrane basement Ge and E. Reuzeau, ly rca oei xrclua tml-epnietasoaino Cdc42 a of translocation stimuli-responsive extracellular in role crucial a plays embryonic normal for required proteins GTPases. related Rho of two regulators Vav, upstream are and development, (FGD1) protein G-eafml nvsua opoeei n disease. and morphogenesis vascular in family TGF-beta signaling. RhoGTPase and 342-353. cytokine of downstream podosomes FGD1. factor, exchange nucleotide guanine nagoesnI-nue mice. complications and II-infused progression angiotensin aneurysm in aortic inflammatory Combadie against G., protects activity Offenstadt, J., Huang, 842-857. L. a J. gene: Gorski, syndrome) and (Aarskog-Scott factor. S. exchange dysplasia nucleotide R. guanine faciogenital Wilroy, Rho/Rac the putative W., of T. characterization Glover, E., R. 567. ciaino 1porsin N ioe-ciae rti iae n actin and kinase, protein FGD1. mitogen-activated factor exchange JNK the by progression, assembly G1 filament of Activation invasion. cell proteolytic directly Dysplasia, shape. Faciogenital cell for modulate to responsible mAbp1 GEF and 1981-1993. cortactin Cdc42 with the interacts Fgd1, (2003). FGD1. factor, exchange nucleotide guanine ‘turning Cdc42 a 241-251. a establishes of pathway switch’ degradation off FWD1/beta-TrCP-mediated The (2005). h euaino iseremodelling. tissue of regulation the c-Jun factor-stimulated growth migration. epidermal cell and in activation factor, kinase NH2-terminal exchange nucleotide guanine n As aiae n rcal agt o acrtherapy? cancer for targets tractable and validated GAPs: and B. Vogelstein, requires 3-phosphate phosphatidylinositol oligomerization. domain to FYVE domain not 8587. FYVE but phospholipid a intact of binding affinity 20) o-ydoi -ikdmna eadto soitdwt missense a with associated gene. FGD1 retardation the in mental (P312L) X-linked mutation Non-syndromic (2002). domain. FYVE the by docking assembly. actin complex-mediated Arp2/3 in pathogenesis. in paradox a development: Res. aneurysm Vasc. aortic thoracic in signaling beta 582 cells. endothelial aortic primary 3582-3594. in Ge podosomes of and rosettes I. induces Kramer, E., Reuzeau, McGraw-Hill. NY: York, New switch. the on turning GTPases: 2093-2101. , 20) o-mdptwy nTFbt signaling. TGF-beta in pathways Non-Smad (2009). 46 119-137. , (2001). 20) hshtdlnstl3popaercgiinadmembrane and recognition 3-phosphate Phosphatidylinositol (2006). m .Md Genet. Med. J. Am. nt E. ´not, h eaoi n oeua ae fIhrtdDiseases Inherited of Bases Molecular and Metabolic The nu e.Cl e.Biol. Dev. Cell Rev. Annu. 20) unn uloieecag atr o Rho for factors exchange nucleotide Guanine (2002). 20) Gbt-nue nohla oooe mediate podosomes endothelial TGFbeta-induced (2009). 20) h Tae ncne elbiology. cell cancer in GTPases Rho (2008). .Ci.Invest. Clin. J. ici.Bohs Acta Biophys. Biochim. .Bo.Chem. Biol. J. ee Dev. Genes nt E. ´not, a.Rv o.Cl Biol. Cell Mol. Rev. Nat. ln Genet. Clin. r,C,Re C., `re, 152A 21) L3rgltsbn development bone regulates MLK3 (2011). 20) ucnletedteilclsform cells endothelial Subconfluent (2005). 21) erdn eie:ivdsmsin invadosomes devices: Degrading (2011). 20) rnfriggot atrbeta factor growth Transforming (2006). il hr.Bull. Pharm. Biol. 16 313-318. , Biochemistry 20) arxmtlortiae and metalloproteinases Matrix (2007). 120 21) inln ymmeso the of members by Signaling (2010). 273 1587-1609. , 20) rnfriggot factor- growth Transforming (2009). 20) feto g1o cortactin on Fgd1 of Effect (2004). .Bo.Chem. Biol. J. na .e al. et L. ´nia, 422-432. , 61 16782-16786. , il hr.Bull. Pharm. Biol. o.Cl.Biol. Cell. Mol. 21) oeo G1 Cdc42 a FGD1, of Role (2011). 10 139-145. , 21) a uefml GEFs superfamily Ras (2010). 19) aigntldysplasia Faciogenital (1996). Cell 185-211. , 1761 21) rln-ihdomain Proline-rich (2010). ur Biol. Curr. 19) D4 n FGD1 and CDC42 (1998). rnsCl Biol. Cell Trends .Cl Sci. Cell J. 43 79 .Ci.Invest. Clin. J. Biochemistry 868-877. , 2422-2427. , u.Ml Genet. Mol. Hum. 669-678. , elRes. Cell 19) slto and Isolation (1994). 8 a.Rv Cancer Rev. Nat. 33 221-233. , x.Cl Res. Cell Exp. o.Cl.Biol. Cell. Mol. 273 35-39. , 21) TGF-beta (2010). 6 ee Cells Genes 18 122 15453-15457. , 1628-1633. , 20) High- (2001). 34 4689-4697. , 19 ,4311-4318. 54-60. , ESLett. FEBS 121 128-139. , 40 20 8581- , (1998). 4383- , 556- , 307 10 12 10 26 J. , , , , , .