ioaD rneci,HlyhHmd* on lno,PasuSha n oan Ivaska Johanna and Sahgal Pranshu Alanko*, Jonna Hamidi*, Hellyeh Franceschi*, De Nicola update the – traffic Integrin COMMENTARY n erdcini n eimpoie htteoiia oki rpryattributed. properly is work original the Attribution that Commons provided Creative medium the any of distribution in terms use, reproduction the unrestricted and under permits distributed which article (http://creativecommons.org/licenses/by/3.0), Access License Open an is This work Finland. ` this 20521, to Turku equally Turku, contributed of authors University *These Biotechnology, complementary for Centre Turku important and turnover, an adhesion integrin–ECM offers regulating for including integrins mechanism levels, of of several Endocytic many on trafficking proteins. regulation intracellular of achieved with binding The and be engagement ligand associated function, can cancer. function is physiological including integrin activity conditions normal integrin integrin pathological for of misregulated regulation paramount and tight is such, signalling As of existence the organisms. for indispensable multicellular many are mediate and the receptors, alone, signals surface intracellular integrins to cell key that other ECM with clear combination the now in is or linking their it complexes However, denote cytoskeleton. they membrane to actin integral named erythrocytes; extracellular originally as from the were role for apart Integrins receptors (ECM). types adhesion matrix cell principal all the and constitute receptors in surface expressed cell abundant are most the among are Integrins Introduction crosstalk Migration, researchers Signalling GTPases, Invasion, Rab of Trafficking, Integrin, number WORDS: KEY growing update. an the with traffic provide integrin in interested to would it felt appropriate we field, in the be in advances Commentary a the With a traffic’. Nearly ‘Integrin wrote entitled cancer. we in ago especially a in decade conditions, relevant pathological is traffic Furthermore, of integrin Thus, number apparatus. integrin cells. of in signalling regulators expression and crucial stability cell as emerging are the pathways is endosomal to traffic that linked cell appreciation growing the the intimately within with receptors expanded adhesion been translocate now has to means a integrin as of an concept traffic as initial The such cytokinesis. is processes and invasion during migration, receptors, cell signalling, integrin–ECM cellular regulate integrin thus to and cells of interactions, that by employed trafficking events mechanism signalling exocytic important intracellular and of rapid through endocytic adhesions, array of remodelling Dynamic vast fate. cell determine a triggers cell the Integrin– and for anchor expression. physical multicellular tissue a provides exist and interaction of extracellular-ligand heterodimers specificity existence substrate integrin differing different the with 24 for vertebrates, indispensable In organisms. are and matrix extracellular (ECM) that the for molecules receptors surface adhesion principal cell the transmembrane constitute of family a are Integrins ABSTRACT uhrfrcrepnec ([email protected]) correspondence for Author 05 ulse yTeCmayo ilgssLd|Junlo elSine(05 2,8982doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal | Ltd Biologists of Company The by Published 2015. ora fCl Science Cell of Journal euaino nerntafc nadto,w aecompiled have we the addition, in In findings traffic. newest integrin the describe of In will how cell. regulation and the we in cell Commentary, regulated a spatially this and of tightly apparatus is metastasis. signalling trafficking integrin and and wired cytoskeletal deeply invasion is the trafficking cell into integrin how therefore, highlights and, data Mounting traffic regulators integrin crucial well- being of identified as mutations has and field oncogenes cancer the known in cell. progress a of conceptual close thus apparatus Importantly, the signalling and and and cytoskeletal expanding regulation the traffic rapidly with connection integrin is of of pathway complexity number this the reveals the of regulators traffic, identified key machineries integrin cellular as and of proteins signalling relevance and adaptor biological integrin the specific interest increasing on controlling With surface. cell tightly the at by availability heterodimer signalling, integrin thus eea xmlso h oeo nerntafci different in traffic integrin cancer on of focus 1). (Table particular role metastasis a the with conditions, of pathophysiological examples several tml n h arx(rdeae ta. 02 awl and Caswell internalisation highly 2012; integrin are of al., route et that the (Bridgewater Importantly, pathways on 2006). as matrix Norman, well are the as traffic type, these and cell integrin and stimuli cellular cases, heterodimer of integrin most the unappreciated regulation on evident dependent in the previously is that, in It and and involved 1). clathrin-independent are distinct (Box components by 2014) various internalisation al., signalling that and et receptor integrin dorsal 2011) (Lakshminarayan factor of carriers al., circular growth et routes by from (Gu New triggered (CDRs) macropinocytosis endosome 2014). ruffles early al., include the et endocytosis bypass (Chen tubular from that compartments directly endosomes or 2012) Arf6-containing late al., from et recycling Reports (Dozynkiewicz integrin documented. endosomes demonstrated have been rapidly years have is recent dogma from context-dependent general picture and the this to cell-type- evidence, variations and complexity, new in emerging adhesions developing With new fresh generate constant 1). and a matrix with the (Box engage cell 2009; to the al., distinct integrins provide of to et temporally pool 2010) Morgan Fiore, and Di 2006; spatially and Norman, Scita two and of to (Caswell back one mechanisms recycled receptors by are integrins integrin membrane Instead, most the degraded. though be to even not sections), appear discussed activity following are of integrin (examples the cells half-life to in migrating coupled long in dynamics is overall trafficking receptor pathway and that the degradative suggest to the now was due through studies or degradation several time constitutively integrin However, long degradation of integrins. a are role determines for The integrins receptor. neglected that the surface of and sorting recycling routes cell endosomal caveolin-mediated or – undergo clathrin- to true through extent holds endocytosed still which large – traffic integrin a of model classical the In trafficking integrin Canonical ` 839

Journal of Cell Science b a humans in conditions receptor pathophysiological associated and Integrin pathways traffic Integrin 1. Table COMMENTARY 840 are Invadopodia integrins. contain also that contacts fibrillar actin- matrix tensin-rich specialized stable represent rich centripetal and filopodia long and the very Invadopodia of adhesions. and formation cytoskeleton the to actin leads the to the The of translocation ECM complexes. to the focal serves (FAs) adhesions anchor of focal into formation complexes focal and the of adaptor maturation and of newly recruitment proteins in the integrins signalling to of leads adhesions Clustering nascent 2012). formed Serini, and (reviewed Valdembri subtypes stability in several and composition into protein morphology, classified on based be can adhesions traffic Integrin–ECM integrin membrane and adhesions altered Integrin–ECM to of machinery. crosstalk cytoskeletal ability the receptor ligation, and this matrix and dynamics the below, from three- activity signals discussed dictate multiple and as GTPase of and integration (2D) to the migration, two-dimensional requires cell shown promote (3D) been to dimensional receptors has these recycling and b b a b a a a a a a a a 5 y1/eyln ratcne,pnrai acrIvso,mtsai,poor metastasis, Invasion, cancer pancreatic cancer, Breast breast cancer, stomach cancer, Lung Myo10/recycling Rab5/endocytosis 1 1 1, 1, v 1, 5 9 5 5 5 5 3 b a b b b b b b b b b A1edctssBes acr rlcne,colon cancer, oral cancer, Breast HAX1/endocytosis 6 v 1 1, a2/eyln vra acr ratcne,colon cancer, breast cancer, Ovarian Rab25/recycling 1 r6rccigAoa eeomn and development Axonal Arf6/recycling 1 C/eyln ratcne,mtn p53 mutant cancer, Breast RCP/recycling 1 LC/eyln vra acr acetccancer, pancreatic cancer, Ovarian CLIC3/recycling 1 1, 1, 1, a b b b 2, a2edctssEihla vra acr prostate cancer, ovarian Epithelial Dab2/endocytosis 3 ubedctssBes acr o-ml ellung cell non-small cancer, Breast Numb/endocytosis 3 3, a a a a 2 IC/noyoi ratcne,oaincancer, ovarian cancer, Breast GIPC1/endocytosis 6 v 5 a a b b b 5, 6 RD/eyln ratcne,pott cancer, prostate cancer, Breast PRKD1/recycling 3 1, T6adVM3rccigBes,cln ie,pancreatic, liver, colon, Breast, VAMP3/recycling and STX6 1 b a 4 6, rfikn tpPtohsooia condition Pathophysiological step trafficking molecule/ Associated a2/noyoi rsaecne,ln acrMgain yoiei and cytokinesis Migration, cancer lung cancer, Prostate Rab21/endocytosis a1/eyln kncrioeei,Barrett’s carcinogenesis, Skin Rab11/recycling a 5 b nernhtrdmrtwrstecl body cell the towards heterodimer integrin 1 cancer ypai,mtn 5 carcinomas p53 mutant dysplasia, acnm,bes cancer breast carcinoma, nasopharyngeal cancer, cancer acr aiaygadcarcinoma gland salivary cancer, acr netnlneoplasia intestinal cancer, system nervous peripheral in regeneration acnm fteha n neck and head the of carcinoma cell squamous carcinomas, ratcancer breast ati acr acetccancer pancreatic cancer, gastric cancer skin cancer, gastrointestinal oge evcl ugadgastric cancers and lung cervical, tongue, testicular, skin, bladder, prostate, mlmne nflpdat rmt elivso ean obe is to pathway remains recycling invasion cell similar promote investigated. a to degradation Whether, filopodia matrix in 2014). implemented and al., invasion et cell (Frittoli in resulting of invadosomes, induction Rab5-dependent and for necessary (HGF)- be factor to growth shown hepatocyte been has pathway recycling Rab4 particular, a recycledalong Macpherson in 2012; al., 2014); a be al., al., et et can (Dozynkiewicz et as pathway MT1-MMP (Arjonen same the occurs and recycling along integrins integrin invasion Intriguingly, increased 2014). cell of al., filopodia-driven et consequence (Monteiro whereas recycling MT1-MMP active 2013), on dependent be Li, appearsto invasion and cell invadopodia-mediated Machesky features, similarities common 2014; some and al., share filopodia et and invadopodia (Arjonen Although 2010). invasion cell cancer in implicated recently matrix been have 1 that structures integrin-dependent Filopodia type are MMP14). transmembrane as the known also by (MT1-MMP, metalloproteinase degradation ECM sites are active and 2011) of al., et (Linder cells invasive to confined typically nain eatssL ta. 99 age l,2011; al., et Yang 1999; al., et Li References metastasis Invasion, significance clinical and process Biological nainadmtsai ehrte l,20;Goldenring 2005; al., et Gebhardt metastasis and Invasion nainadmtsai o ta. 94 oge al., et Tong 1994; al., et Mok metastasis and Invasion epatctransformation, Neoplastic rlfrto,po rgoi aoaoe l,20;Pc tal., et Pece 2007; al., et Maiorano prognosis poor Proliferation, nainCege l,21;Cege al., et Cheng 2010; al., et Cheng Invasion iserpi v ta. 02 v and Eva 2012; al., et Eva repair Tissue nainadmtsai a ta. 02 il ta. 2009; al., et Mills 2012; al., et Dai metastasis and Invasion nain orponssDzniwc ta. 2012; al., et Dozynkiewicz prognosis poor Invasion, nainadmetastasis, and Invasion rlfrto,ivso iee ta. 09 ag tal., et Jaggi 2009; al., et Eiseler invasion Proliferation, rlfrto ig ta. 2012 al., et Riggs Proliferation prognosis aneuploidy of generation prognosis poor metastasis, invasion, aclrdevelopment vascular ora fCl cec 21)18 3–5 doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal b -nernM1MPco-trafficking 3-integrin–MT1-MMP roe ta. 04 a tal., et Cao 2014; al., et Arjonen Ho ae ta. 05 asye al., et Ramsay 2005; al., et Bates iioh n ao,2002; Katoh, and Kirikoshi ¨gna ue l,1999 al., et Yu al., et 2008 Pellinen 2006; al., et 2014 ta. 99 ulre l,2009 al., et Muller 1999; al., et ta. 2014 Xu al., 2002; et al., et Wang 2010; 04 etofe l,2009 al., et Westhoff 2004; 07 rbnk ta. 2010 al., et Trebinska 2007; a ta. 2010 al., et Nam 2011; Nam, and 2006; Goldenring al., et Fan 2012; al., et Dozynkiewicz 2004; act,2014 Fawcett, ulre l,20;Zage al., 2009 et Zhang 2009; al., et Muller apesne l,2014 al., et Macpherson uese l,2006; al., et Muders aesye l,2008 al., et Yavelsky 2009; al., et Valdembri 2008; al., et Rudchenko hbli ta. 2011 al., et 2006; Shabelnik al., et Ristich 2003; se l,21;Pellinen 2012; al., et ¨s

Journal of Cell Science COMMENTARY osbytgte ihitgis(oykeize l,21) to together 2012), findings, These 2011). al., lysosomes, al., et et (Sung and migration (Dozynkiewicz cell endosomes integrins promote with late endocytosed together from possibly the re-secreted environment, is ECM low-fibronectin fibronectin a without In 2011). directing feasible for of crucial size is be proteolysis, the MT1-MMP Therefore, by regulated components, fibrils. not ECM detachable fibronectin is of would cleavage proteolytic ECM, co-endocytosis Chandler, integrin– fibrils, and the fibronectin fibronectin of (Sottile size degradation large the lysosomal given of example, However, 2005). for targeted For component is and ligands. fundamental co- matrix with endocytosed supports a with vesicles integrins fibronectin, endocytic of in presence endocytosis molecules The traffic. extracellular integrin of a stages of is of initial endocytosis, the detachment receptor in allow step complete necessary to substrates, and/or their molecules from integrins ECM of Processing traffic integrin in ECM ahasfcltt deintroe n rvd h elwt osatfehpo fitgist naetemti n eeaenew generate and matrix the engage to integrins recycling of These pool surface. fresh cell constant the a to with returning long- cell to the the entering prior receptors provide (PNRC) Alternatively, membrane. and compartments short-loop plasma the turnover recycling adhesions. the through Recycling adhesion to perinuclear 2010). back Rab11-positive facilitate Fiore, receptors Di to pathways of and delivery relocate Scita rapid 2009; pathway promotes al., loop and et Morgan dependent 2006; Rab4 Norman, is and pathway (Caswell yello pathways 2014). the long-loop al., by and et short-loop (indicated (Lakshminarayan galectin-3 endocytosis protein receptor carbohydrate-binding clathrin-independent the In of and Here, signalling. domain membrane cell. extracellular receptor glycosylated cell plasma the factor the the of apical with growth surface interacts the by figure) extracellular triggered on the the in both projections star at 2014), membrane initiated al., F-actin-rich is et 2011), pathway identified (Mai dependent Newly al., endocytosis figure). et clathrin-mediated (see (Gu of independent (CDRs) clathrin form addition, and RhoA-dependent ruffles dependent a dorsal clathrin and circular as surface, from classified broadly macropinocytosis routes include several pathways by occur can endocytosis trafficking Integrin integrin Canonical 1. Box nernrccigbc otepam ebaeocr hog n ftosailyadtmoal itntmcaim fe eerdt as to referred often mechanisms distinct temporally and spatially two of one through occurs membrane plasma the to back recycling Integrin b nerncnb noyoe i ltrnidpnetcrir.I otatt te noyi ots hsgyopiglpd n actin- and glycosphingolipid- this routes, endocytic other to contrast In carriers. clathrin-independent via endocytosed be can integrin 1 b nern nacvoi--eedn manner caveolin-1-dependent a in integrins 1 a

Extracellular matrix Extracellular matrix Cytosol 5 b nernedctss(h n Sottile, and (Shi endocytosis integrin 1 Integrin internalisationroutes Macropinocytosis Internalisation Lysosomes Nucleus Early endosome Inactive Rab4 α Short-loop pathway v β 3 integrin aelnRhoA Caveolin β PNRC 1 integrin b nernadhsbe ugse opooemcaia eomto of deformation mechanical promote to suggested been has and integrin 1 agadMNvn 02,sgetta arxtroe and turnover matrix levels. multiple that on coupled suggest be can 2012), traffic integrin McNiven, and 2014; al., et Wang (Stehbens FAs be in occurs to also invadosomes, thought to previously restricted degradation, ECM that observations with nohla el,RsadRbitrco RN)regulates (RIN2) 2 interactor understood, In Rab described. well and been Ras not have cells, examples currently endothelial specific adhesion- some is of nevertheless nature trafficking exact the and type-specific assembly Although the processes. during employed turnoverdisassembly are alternative adhesion routes that trafficking suggesting dynamic integrin rates, turnover mentioned of differing subtypes, exhibit adhesion process different above, The 2009). this al., et (Caswell of to central being regulation recycling cell integrin–ECM integrin the the with of retraction migration, and cell of ECM during the rear protrusions to membrane disassembly tension of of application stabilisation the and the and for crucial assembly is adhesions dynamic turnover adhesion The cell–ECM and traffic Integrin RCP Rab11 Active α Long-loop pathway 5 β 1 integrin ora fCl cec 21)18 3–5 doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal β 1 integrin Integrin Clathrin Clathrin-independent carriers 841 w

Journal of Cell Science euae h erimn ftlnadvnui oFsb local by FAs PtdIns4,5 to vinculin of and talin variant of PIPKI production This recruitment 2002). the al., et impairs regulates (Ling assembly and PIPKI FA FAK, to in implicated contrast and in 2 Interestingly, migration. dynamin cell between of formation Depletion complex 2010). al., et (Chao PIPKI disassembly FA drive therefore active of endocytosis nF unvr PIPKI implicated been turnover. have these FA of two and in cells, mammalian in exist rPIPKI or Np;acl ufc eetr pcfclydrives specifically receptor) surface GAIP cell adaptor a the neuropilin-1(Nrp1; and of (GIPC1) 1 consisting member C-terminus protein complex interacting 2012), endocytic al., et an (Sandri whereas adhesions nascent from endocytosis integrin COMMENTARY ci,itreit iaet n irtbls–adtheir in implicated and been 842 – have turn, microtubules in and motors, the molecular filaments cell to associated the – intermediate of cytoskeleton leads organisation cellular actin, the the of ligands on components impinge Different extracellular cytoskeleton. that signals by of initiation engagement traffic integrin Integrin and cytoskeleton cell The by (encoded isoforms PIPKI Three kinases 2006). PIP5K1B Ling phosphate in al., (reviewed phosphatidylinositol adhesion et integrin–ECM to I response in type (PIPKI) by membrane ucinlydsic ol fPtdIns4,5 of pools distinct functionally unvro A,adcneunl nacdcne cell affects cancer adversely into and accumulation endosomes enhanced syntaxin-6 levels recycling triggers and cholesterol Rab11-positive network consequently of trans-Golgi size Inhibition the 2013). and in Rab8a- number, al., et FAs, and increased (Kanerva migration protein) in of C1 resulting turnover (Niemann-Pick fashion, an in NPC1- endosomes dependent late lipase, from FAs to acid recruited is (LDL), lipoprotein 2010; or al., et 2002). (Chao assembly process al., C-terminal this et in Ling PIPKI implicated clear, FA been is of yet have not isoforms domains modifications is in PIPKI sites post-translational FA two to however these specifically involved of targeted and activity coordinated proteins the How disassembly. of recruitment ta. 09.Tetreigo hs rtist deinstsis sites Ezratty adhesion of production to (PtdIns4,5 2005; restricted 4,5-bisphosphate proteins phosphatidylinositol spatially al., these the et of on FA dependent targeting Ezratty fundamentally regulate The 2009; to 2009). and shown al., Kunz, et been (Dab2) and have disabled-2 kinase (Chao microtubules, clathrin, turnover as adhesion PTK2), well focal as as active AP2, dynamin-2, known ligand-bound as also of (FAK, such endocytosis to Proteins linked integrins. be to conditions, 2009). al., et (Valdembri adhesions fibrillar from endocytosis 04.Arl o ytxn6in syntaxin-6 for role A 2014). and n h nerto fcoetrlit ifrn membrane different into cholesterol of FA FA uptake integration controlling cholesterol compartments. on of in rate the the effects on traffic dependent and cholesterol-mediated be to cholesterol of likely is and turnover degree 2011). Golgi The al., the dynamics. intriguing an et for highlight step and recycling Tiwari network role integrin trans-Golgi 2012; new the traverses a al., that identify studies et these (Riggs Importantly, endothelial and respectively cancer chemotactic cells, in demonstrated been also has nmmaincls hlseo,i h omo low-density of form the in cholesterol, cells, mammalian In Adssebyhsbe ugse,udrsm specific some under suggested, been has disassembly FA a 5 b b nernrccigadcl irto Rvre tal., et (Reverter migration cell and recycling integrin 1 lcscahi sebya deinpaus prevents plaques, adhesion at assembly clathrin blocks c and 6 a ucina pcfcpafrsfrthe for platforms specific as function can 661 PIP5K1C b nernfo yi-oiieFsand FAs zyxin-positive from integrin 1 nhmn)admlil pievariants splice multiple and humans) in b P 2 a ensont eit the mediate to shown been has a Lgt ta. 01.Thus, 2011). al., et (Legate 3 b and 1 P a 2 5 b rdcdb PIPKI by produced nerntrafficking integrin 1 P b 2 PIPKI , tteplasma the at ) a 5 b PIP5K1A integrin 1 c 6 is 661 a v b b 3 , h euaino deintroe hog ieto indirect or direct recycling. through and/or endocytosis turnover integrin adhesion of modulation of regulation the soitdctpamclne soitdpoen n 2 through turnover and and disassembly 1 FA microtubules triggering tether proteins thereby to shown FAs, Microtubule- been to associated have 2014). CLASP2) an linker and al., through (CLASP1 dissolution cytoplasmic et FA (Yue associated enhance MAPRE2) mechanism to as its shown kinase known Arf6-dependent through been also FAs protein has (EB2, microtubule- to 2 protein 2009; (MAP4K4) mitogen-activated end-binding recently, al., 4 with kinase Very the interaction et kinase 1). (Ezratty of kinase (Fig. (MAPK) turnover nevertheless delivery 2002) FA membrane, al., mediated of plasma et rate the Kaverina the or to increase disassembly transport they FA for Although clathrin 1999). required al., for absolutely et (Ezratty Kaverina not site 2009; are al., autosomal adhesion microtubules et integrin–ECM Ezratty molecules, 2005; targeted al., the et adaptor to LDLRAP1) two Dab2, and as and known and with also (ARH, contact hypercholesterolemia clathrin recessive physical local of following the delivery by adhesions, disassembly of FA dissolution trigger dyneins Microtubules proteins polarized kinesins. motor by and microtubule-based guided the is and movement microtubules vesicle intracellular Directed traffic integrin in Microtubules ci nitgi nooa rfi atclryo endosomes. actin and on complex particularly multiprotein for a traffic role (Arp)2/3, is protein regulatory endosomal Actin-related important integrin actin an eukaryotes, trafficking in Although higher indicated actin vesicle in have 2006). endocytosis in studies of al., several role process the et fundamental for (Kaksonen dispensable a endocytosis has and actin yeast, In traffic integrin and Actin the endocytosed traffic, of integrin recycling of motor the terms microtubule In directs by kinesins. KIF1C promoted as kinesin is such vesicles, proteins turnover and organelles FA microtubule-mediated 2013). al., edge, et been leading (Montagnac enhancing the has at pits, stabilization clathrin-coated potentially microtubule promote in to present shown AP2, of with Localisation interaction ( 2014). occur al., 1 is et that to acetyltransferase signal (Stehbens suggested a FAs the by been at guided be located Intriguingly, has to and FAs microtubules metalloproteinases. of in independently of CLASPs of exocytosis accumulation local the ae N nefrnesre sanwrgltro inactive of regulator new kinesin fluorescence-microscopy- a tail another as a KIF15, contrast, screen in a 2012). interference In identified RNA al., recently based a cell. et by of was (Theisen re-establishment the and migration motor, axis well- polarity to cell cell cell a of new polarity loss model, directional to defined leads this maintains retraction In a tail steering’. a assigning in cell ‘rear force traction actin as anchored the resist 2012) described to and al., process mature et to trailing to FAs the necessary (Theisen rear is at integrins allow FAs of cells for delivery role KIF1C-dependent migrating functional Here, new edge. of a highlighting rear 1), (Fig. the to integrin I1,KF5promotes KIF15 KIF1C, nernseii eas a2hsntbe soitdwith associated 2006). been Cooper, and not (Maurer has receptors the other be Dab2 engage of to trafficking because to appears endocytosis membrane specific KIF15-triggered plasma integrin 1). the (Fig. tail to integrin Dab2 of transport 2 h irtbl-eedn eieyo ags uhas such cargos, of delivery microtubule-dependent The b nerntafc(soae l,21) oee,unlike However, 2014). al., et (Eskova traffic integrin 1 ora fCl cec 21)18 3–5 doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal a A1 tpxli-ihahsosadits and adhesions paxillin-rich at TAT1) a 2 b nernedctsstruhthe through endocytosis integrin 1 a -tubulin a 5 b a 1 2

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ECM. same biological the the to different heterodimer to mammals a specificities of in binding binding heterodimers integrin overlapping distinct have functionally 24 The recycling heterodimer Differential N1 n N3 irp nernknln2itrcinby interaction members in integrin–kindlin-2 role family disrupt a nexin SNX31 plays sorting and Dab2 the SNX17 the fibroblasts, compartment, In 2009). in al., endosomal et (Teckchandani (Ezratty whereas disassembly migration FA 2012), microtubule-induced cell during al., receptors et fresh microenvironments, deliver 2D regulates in to Dab2 membrane implicated cells, dorsal endocytosis integrins the HeLa from been ligand-free In endocytosis and types. integrin has cell ligand-engaged different of Dab2 localised in turnover the 2007). of in promotes Kaibuchi, both edge structures. and cell, leading clathrin-coated (Nishimura the migrating to at and AP2 a dephosphorylation, recruitment the Numb integrins, and Subsequent with cell complex, association kinase efficient its protein Par to prevents atypical linked (aPKC) by Numb been C of also Phosphorylation has migration. traffic integrin folding mediated cup might Numb- optic Opo in aid Thus, antagonises (Bogdanovic to motif. localization integrin NPxF OFCC1) polarized Numb integrin-like promote for an as competing through directly known binding (Teckchandani by transmembrane endocytosis (also integrin Dab2 the Numb dependent morphogenesis, Opo and adaptors retina During protein 2007) clathrin 2012). al., to Kaibuchi, et binding and by (Nishimura endocytosis integrin idn otesm ebaedsa nernNx oi as motif NPxY integrin membrane-distal preventing and same kindlin-2 the to binding rfi euain idn fAA1to in ACAP1 found also heterodimer-specific are of (which in 10–15 Binding residues involved cytoplasmic regulation. potentially are traffic and (Bo subunit 2014). mechanism al., unknown et Tseng yet 2012; a al., et by pathway degradative ehns hrb h ciiyof activity the whereby mechanism qal ple othe in to the Rab21 applies of al., to equally et role (Pellinen Similar the cytokinesis by during 2008). particular, exemplified in is and, traffic endocytosis integrin in motif 2007). migration al., cell et cancer on (Ramsay impacts and addition, endocytosis In integrin 2012). triggers to al., et binding (Bai signal HAX-1 recycling a elicits integrins) eyln of recycling a2 o h aebnigst opooeitgi recycling integrin promote to site 2011). al., binding et same (Mai the for Rab21 elmigration, cell aelpdafrainaddrcinlypritn elmigration. cell Conversely, persistent directionally and formation lamellipodia irnci,icesdrccigof recycling in rich is increased cells that cancer microenvironment When fibronectin, 3D 2007). a al., through et al., invasively White migrate et 2013; al., (Danen et pathway Morgan 2005; Rho–ROCK–cofilin a through migration hog h eraiaino h ci yokltnadcell and pseudopods cytoskeleton long of actin extension the the by characterized of – morphology reorganization the through nthe In te escnevdmtf aebe dniido the on identified been have motifs less-conserved Other nthe On b ora fCl cec 21)18 3–5 doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal a a uui,teNx oishv ensont regulate to shown been have motifs NPxY the subunit, 5 ta. 02.Ti pta etito fNumb- of restriction spatial This 2012). al., et ´ sbnt h motneo h osre GFFKR conserved the of importance the -subunit, b a a and 1 5 5 b b a nern(ht ta. 07.I h otx of context the In 2007). al., et (White integrin 1 nernrccigidcsfs admcell random fast induces recycling integrin 1 v b nernrccigspot Rac-dependent supports recycling integrin 3 b a nernbtenrsde 3 n 758 and 731 residues between integrin 6 v a b b sbnt hr AA optswith competes RASA1 where -subunit, .Svrlsuishv eosrtda demonstrated have studies Several 3. b sbnt h ocp fcompetition of concept the -subunit, nernfo rgesn ln the along progressing from integrin 1 a a 5 v b b rmtsinvasion promotes 1 nernsuppresses integrin 3 b nernat integrin 1 b b integrin 1 and 3 ¨ttcher 847 b b 5 -

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Fig. in summarized are and below nerni rtuin fivdn el.Hwvr h interaction the However, cells. invading of protrusions in integrin smdae ythe by mediated is hog atsotlo eyln ot htivle a4and Rab4 involves that of route association recycling the short-loop fast a through this of specificity heterodimer and the heterodimers, explain integrin pathway. not different does several by therefore shared is which fetr n h usqetfraino rabaptin-5–Rab5– triggers a complex of This of 2012). delivery stimulation al., formation et PDGF (Christoforides subsequent complex Rab4 2004). the Rab5 al., and (a rabaptin-5 effector) et of phosphorylation (Woods PKD1-mediated promotes PRKD1) as known o essetcl irto n an and migration cell persistent for r-eitdsnea- hshrlto,increased phosphorylation, syndecan-4 of absence the Src-mediated directionally In matrices. and Arf6-dependent cell-derived on stabilization migration cell FA persistent and increased factors) (a and to growth activation leading traffic recycling, and syndecan-4 Arf6 integrin molecules ECM of to inhibits for linked phosphorylation receptor been proteoglycan Src-mediated also has migration. to it also Interestingly, but dynamics. signals adhesion extracellular and multiple traffic integrin integrate modify to functions that receptors only factor indications not growth clear and are integrins route between there trafficking crosstalk Nevertheless, this addressed. the into However, not feeds of 2014). was in signalling al., recycling factor migration et growth the cell (Majeed whether cells for promote cancer to necessary lung and be fast-migrating light-chain integrin to clathrin inactive shown the endocytosed with been complex also HIP1 in adaptor HIP1 has clathrin 2014). the al., and et RhoA (Mai clathrin, in requiring Matrigel process 3D in a migration cell been of collective has integrin-dependent HGF and responses rapid study, induce another context-dependent (Gu In to exist. shown that macropinocytosis factors by growth suggesting to surface, integrins 2011), cell al., dorsal actin-dependent et the CDRs, been from at also endocytosis has structures integrin PDGF content in Interestingly, fibronectin 2012). implicated low al., et with (Christoforides microenvironments into invasion oeta otafcigo hs eetr Zmemn tal., et (Zimmermann receptors these 2005). of co-trafficking and potential (FGF) factor growth migration fibroblastic b recycling of cell syndecan-4 accumulation of the inhibits Disruption to 4). leads and (Fig. 2013) al., turnover et (Morgan FA accelerates recycling nerni ydcncnann nooe,suggesting endosomes, syndecan-containing in integrin 1 nsm ae,rccigo pcfcitgi eeoieshas heterodimers integrin specific of recycling cases, some In r satrsn iaeipiae nmn acrtypes. cancer many in implicated kinase tyrosine a is Src a v a b v nernt h edn deo irtn cells migrating of edge leading the to integrin 3 b -to 3- a v b b yolsi al(awl ta. 2007), al., et (Caswell tail cytoplasmic 1 ihtePCrltdkns K1(also PKD1 kinase PKC-related the with 3 b a a nernedctsst rv protease- drive to endocytosis integrin 1 5 5 b b and 1 -eitdrccigaedescribed are recycling 1-mediated a a v a v b v b nern u not but integrin, 3 b ne h NCadare and PNRC the enter 3 -eedn oeo cell of mode 3-dependent a 5 b integrin 1 a a a 5 5 5 b b b 1, 1 1 nicesn ubro tde aelne nernendosomal integrin importance. linked biological how have its studies of as of understanding well number our increasing as An regulated in is made traffic been integrin have advances Major perspectives future and Conclusions with upesrp3o h irpinof disruption the or p53 suppressor niiosreleases inhibitors omn 08 ulre l,20;Rieoe l,21) C and RCP and 2012). al., (Caswell et pseudopods Rainero phosphatidic-acid-rich 2009; a cell al., invasive to et Muller of 2008; recycling Norman, tip the its at promotes membranes and integrin erimn oIGP tteivsv rn.Ti pathway This front. invasive its the triggers at so of IQGAP1 activation and the to RacGAP1 through phosphorylates recruitment membrane PKB plasma PKB/Akt. the downstream and on trafficking signalling regulate further to EGFR1, including at yehnigRCP-dependent enhancing by future. part, the in be investigation will for this cell and topic linked integrin cancer interesting be Thus, to an drive 2004). appear al., formation and filopodia et and Zhang structures traffic 2014; al., these et of (Arjonen cancer invasion stability to pancreatic myosin-X the of and ability enhance the breast to integrin linked is in transport This 2014). filopodia invasion al., enhanced et cell (Arjonen to be and leading myosin-X, to formation of filopodia. protein expression remains induces filopodial also formation the resemble p53 mutant filopodia Interestingly, that influences determined. activation increased spikes Rho how actin These However, 2013). contain al., into et protrusions migration the (Jacquemet invasive promotes matrices and switch fibronectin-containing protrusions Rac-to-RhoA pseudopod The of front. and extension cell the activity subcellular at specific Rac these regions in suppresses locally RhoA recycling activates concomitantly integrin of downstream fitgist eit h prpit elbehaviour. factor cell appropriate growth the mediate distinct partner to recycling that integrins RCP the of and and endocytosis and both linked MET determine is signals intimately of It pathways are 2014). trafficking al., integrin the et that (Muharram possible migration therefore cell and proliferation, and survival, Thus, growth MET cell endocytosis. tumour promotes its coupling complex inhibiting tensin-4–MET possibly by the MET MET, stabilizes and active an integrin, with Tensin-4, and interacts MET 2013). between and link al., additional MET- known an a et a in and HGF (Muller oncoprotein signalling, to MET response manner in enhanced of RCP-dependent scattering to recycling cell leading the and receptor, in invasion HGF implicated been the have MET, mutants p53 addition, a h naoitcatvte fRc n hAdwsra of on downstream dependent RhoA and are by Rac1 that of occur activities reorganization antagonistic can the actin invasion in and changes cell morphology al., dramatic by cell Cancer et characterized are (Caswell 2009). that mechanisms membrane al., Rab11 several the et as which to Muller known back determines 2009; recycled also (RAB11FIP1)] is association [RCP; protein-1 heterodimer Integrin protein interacting microenvironments. Rab-coupling family 3D cancer the of in mode with the invasion regulating mechanism cell crucial a as identified and acrclsepesn both expressing cells cancer 5 v sdsrbdaoe uatp3poen rmt nain in invasion, promote proteins p53 mutant above, described As ifrnilrccig hc eemnsteboviaiiyof bioavailability the determines which recycling, Differential b b nerncoeaieyrcutrcpo yoiekinases, tyrosine receptor recruit cooperatively integrin 1 and 3 a a 5 v b b nernsgaln,rsetvl.I irbat and fibroblasts In respectively. signalling, integrin 1 ora fCl cec 21)18 3–5 doi:10.1242/jcs.161653 839–852 128, (2015) Science Cell of Journal nern ano-ucinmtnso h tumour the of mutants Gain-of-function integrin. 3 a 5 b nern oegg arxlgns a lobeen also has ligands, matrix engage to integrins 1 b b oflpdatp hr integrin-adhesions where tips filopodia to 1 -soitdRP C hnbnsto binds then RCP RCP. 3-associated b -nernbnigprnr provides partner, 1-integrin-binding a a 5 v b b eyln n downstream and recycling 1 and 3 a b a 5 nerntafc Tensin-4 traffic. integrin 1 v b a b nernrccig In recycling. integrin 1 5 ucinusing function 3 b ,RPi associated is RCP 1, a a a 849 v 5 v b b b b b 3 1 1 1 3

Journal of Cell Science ean nopeeyudrto.Hwvr ti la that some of interestingly, and, mediators clear receptors key these is are of traffic proteins it coordinated growth-factor- scaffold the of However, and conditions adaptors details understood. different endosomal the under incompletely as traffic future integrin interesting remains an of the be regulation tyrosine in will induced receptor research and system of and this area into integrins hard-wired between metastasis is and kinases Cross-talk invasion to cancer. recycling its in particular, in and, traffic, COMMENTARY 850 Doctoral Turku the by funded is P.S. Program. supported Doctoral is Research N.D.F. Drug of Fellowship. Short-Term Program the EMBO Doctoral by Turku an the and by Sciences; supported the Biomedical and is Foundation; J.A. [grant Juselius Organization. Grant Sigrid Cancer the Consolidator Finnish Finland; Council of Academy Research the European 615258]; an number by supported is J.I. Funding interests. financial or competing no declare authors The interests Competing ‘Warburg invasion the integrins. also but through that proliferation metastasis cell and and regulate cells only and not invasion cancer might exciting effect’ regulating the in traffic be up differentially could opens integrin migration traffic and This and integrin future. that the traffic metabolism possibility in 2013). investigated between integrin cells, al., be links should et between cancer (Tuloup-Minguez potential breast cancer link The in In a alterations autophagy. metabolic suggesting been and by migration recently recycling, over cell have modulates turn integrins autophagy Furthermore, to (De 2013). actin is shown with al., glycolytic edge cells leading the linked et cell and the tip Bock to properties localize endothelial has to migratory angiogenesis. appear cell’s sprouting enzymes of the evidence the regulation for in important the recent glycolysis to Increased glycolysis Interestingly, cancer and and metabolism survival. proliferation oncogenic regulating cell in the role of one important is integrins field. ligand-engaged the of in regulate questions subset unanswered specifically a major to of cells allow traffic that the mechanisms the are what all shared, by are example, mechanisms specific for traffic integrin elicit established currently the and most of However, expression engagement. ligand following tissue-specific processes aresignalling exhibit poorly heterodimers to integrin only Distinct known towards is heterodimers. specificity any integrin it have certain established, pathways these well whether understood increasingly becoming are of pathway default the cargo. become integrin might inhibition endocytosed or upon degradation that diverted recycling suggests SNX17 This of in is cells. WASH, resulting in lysosomes levels integrin to integrin including trafficked reduced instead the proteins is receptor for unless the by CLIC3, targeted that, or recycling traffic recycled appears towards integrin is It receptor in have the degradation. studies steps whether Several regulatory determine 2014). shape, types that al., important cell cancer et established different determining Mai now many 2013; in al., in factor et capacity key (Jacquemet to invasive a crucial linked and is of been 2009). are mobility and has family which al., signalling, traffic Rho RhoA, integrin integrin et the and of effectors Rac1 of Zhang downstream including activity in 2014; GTPases, the upregulated small are al., of tensin-4, regulation et or Furthermore, RCP (Muharram as such carcinomas adaptors, these of lhuhmn ftemcaitcdtiso nerntraffic integrin of details mechanistic the of many Although ntefedo acr eaoimi ieysuidfrits for studied widely is metabolism cancer, of field the In b nern.Hwseiiiyi salse and established is specificity How integrins. 1 b nernmembrane integrin 1 ue,S .adWlh .D. M. Welch, and N. S. Duleh, den van J., Grindlay, I., Macpherson, B., N. Jamieson, A., M. P.Dozynkiewicz, Carmeliet, and M. P., Georgiadou, Sonneveld, K., Bock, S., De Huveneers, W., Franken, J., Rheenen, van Y. H., Tian, E. Z., G. Danen, Chen, C., Ren, L., Pi, G., Cai, C., Yu, D., Peters, Huang, Y., S., Liu, Bourgoin, Y., T., Dai, R. Premont, M., Porcionatto, A. E., Toker, Bos, J., and Li, C. J., J. Dai, Norman, K., K. Brown, A. E., K. Rainero, Rao, and C., S. Christoforides, Ran, S., Vyakaranam, K., D. Janaki, L., Volk, M., J. Cheng, hn,K . aa,J . u,W . au,A,Ymd,K,Aeseg N., Auersperg, K., Yamada, A., Lapuk, L., W. Kuo, P., J. Lahad, W., K. A. Cheng, P. Randazzo, and X. Jian, R., Luo, W., P. P., Chen, Zhang, Z., Wei, T., Vadakkan, C., A. Daquinag, F., Ashcroft, T., W. Chao, Bogdanovic H., Kawakatsu, B., Wu, E., Maynard, C., Brown, I., D. Bellovin, C., R. Bates, Ho P., Rouhi, E., Mattila, R., Kaukonen, A., Arjonen, ho .T n uz J. Kunz, and C. T. J. W. Chao, Norman, and S. Vadrevu, T., P. Caswell, Bo Hsu, and F. Sun, J., Li, J., Ma, K., Zhang, Q., Zhou, J., Lou, X., J. Pang, M. M., Humphries, Bai, and P. A. Mould, A., P. Buckley, A., J. Askari, J. Ivaska, and S. Veltel, J., Alanko, A., Arjonen, References awl,P n omn J. Norman, and P. Caswell, C. J. Norman, and T. P. Caswell, rga fMlclrMdcn TDM.Dpstdi M o immediate for PMC in Deposited (TuDMM). release. Medicine Molecular of Program awl,P . pne .J,Pros . ht,D . lr,K,Ceg .W., K. Cheng, K., Clark, P., D. White, M., Parsons, J., H. Spence, T., P. Caswell, a,R,Ce,J,Zag . hi . ig . ig . hn,L,Mlk .S., Y. Malik, L., Zhang, W., Xing, X., Qing, Y., Zhai, X., Zhang, J., Chen, R., Cao, yo,A,Hmhis .D,Akr,J . ri,S . ol,A .and P. A. Mould, E., S. Craig, A., J. Askari, D., J. Humphries, A., Byron, T. P. Caswell, and C. J. Norman, E., R. Bridgewater, thr .T,Srme,C,Mvs . ee,H,Wdae,M,Teg .Y. H. Tseng, M., Widmaier, H., Meyer, A., Meves, C., Stremmel, T., R. ttcher, ¨ nooe/yooe n rv acrprogression. 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Journal of Cell Science ig . ogmn .L,Frsoe .J,Bne .W n nesn .A. R. Anderson, and W. M. Bunce, J., A. Firestone, L., R. Doughman, K., Ling, M. Himmel, and C. Wiesner, S., Linder, Y. Chen, and H. Feng, Y., Li, V. L. Parise, and K. M. Larson, P., S. Holly, iee,T,Do Casanova, T., and P. Eiseler, Melancon, K., T. Lasell, K., Ly, R., Moravec, L., J. Dunphy, COMMENTARY eae .R,Tkhsi . oadr . ar,B,Betgr . et R. Zent, D., Boettiger, B., Fabry, N., Bonakdar, S., Takahashi, R., C., K. Benzing, Legate, T., M. Howes, U., Becken, C., Wunder, R., Lakshminarayan, M. Katoh, and V. H. J. Kirikoshi, Small, and O. Krylyshkina, I., Kaverina, V. J. Small, and P., O. Lappalainen, Krylyshkina, I., R., Kaverina, Bittman, S., Li, T., Blom, L., R. Uronen, K., Kanerva, G. D. C. Drubin, K. and P. Balaji, C. Toret, and M., P. Kaksonen, G. Hemstreet, J., A., D. Smith, Kriegsheim, S., P. von Rao, M., E., Jaggi, R. Bridgewater, M., D. Green, G., Jacquemet, O. R. Hynes, ehrt . riebc,U,Rctr .H,Fu H., K. Richter, F., U., Breitenbach, Bianchi, C., Gebhardt, S., Confalonieri, P., Marighetti, A., X. Palamidessi, Ma, and E., L. Frittoli, B. Chen, Y., X. Xin, G. Y., G. Fan, Gundersen, and E. E. Marcantonio, C., G. Bertaux, J., G. E. Gundersen, Ezratty, and A. M. Partridge, J., E. Ezratty, ffrench- V., Kanamarlapudi, C., J. Norman, R., J. Marland, S., Crisp, R., Eva, J. Fawcett, and R. Eva, T., Lisauskas, A., Arjonen, S., Reusing, D., Matelska, B., Knapp, A., Eskova, Ho B. M. Brenner, and W. V. Hsu, H., E. Noss, Z., Gu, R. D. M. J. Welch, Lee, and and D. E. S. Goley, G. Ray, R., J. Goldenring, T. K. Nam, and R. J. Goldenring, gna ¨ 20) yeIgmapopaiyioio hsht iaetresand targets kinase phosphate phosphatidylinositol gamma adhesions. focal I regulates Type (2002). invasion. cell proteolytic in stomach]. and lung Zhi the Za of carcinoma human of metastasis otoln noyoi fbt1integrins. beta1 of endocytosis controlling E. J. cancer. motility. cell during dynamics adhesion dissociation. and relaxation 1033-1044. their promotes contacts substrate transport membrane route. Rab8a-Myosin5b-actin-dependent a via membrane plasma Pera prostate androgen-independent endocytosis. clathrin-mediated in for down-regulated is mu C cancer. kinase T.Protein P. Caswell, and C. complex. IQGAP1 J. Norman, a J., M. Humphries, migration. cell 110 of regulation precise and activation Cell Rac Biol. for required is ras euae ylclzdPdn(,) synthesis. PtdIns(4,5)2 localized by regulated Fa clathrin- and of al. biogenesis et C. carriers. glycosphingolipid-dependent Lamaze, independent V., Chambon, drives N., Ariotti, Galectin-3 S., Sales, S., Arumugam, eae TaeRb1 nsi carcinogenesis. skin in Rab11a J. GTPase Hess, related and P. al. Angel, et M. program Garre, invasive dissemination. proteolytic I., tumor a promotes Martin-Padura, induces and circuitry G., recycling Viale, RAB5/RAB4 A G., (2014). Mazzarol, C., Malinverno, in disassembly adhesion focal for endocytosis cells. integrin migrating mediates Clathrin adhesion focal and dynamin by mediated kinase. is disassembly adhesion focal induced neurons. DRG adult in growth axon 10352-10364. regulates and integrins W. of J. Fawcett, and C. Constant, integrin. of trafficking endocytic the of regulator novel Sci. al. a Cell et J. J. as Ivaska, KIF15 R., Eils, identifies R., Russell, breast R., Pepperkok, inhibits and expression metalloproteinase invasion. cell matrix cancer regulates D1 kinase i iclrdra ufe n arpnctssdrn tmltdcl migration. cell stimulated Biol. during Cell macropinocytosis and J. ruffles dorsal circular via age. of comes epithelia. Barrett’s carcinogenesis. in cells cancer ovarian epithelial vivo. human in of and growth vitro inhibits RNAi by expression regeneration. and nerntafcidcsaepod n noei rnfraini ir n in and vitro in transformation oncogenic and vivo. J. aneuploidy induces Ivaska, traffic integrin and O. Kallioniemi, 5 b 673-687. , s . um,S,Vle,S,Mtia . Muruma E., Mattila, S., Veltel, S., Tuomi, G., ¨s, eyln upessRcadpooe hAatvt i h RacGAP1- the via activity RhoA promotes and Rac suppresses recycling 1 nn . aoo .adIoe,E. Ikonen, and G. Raposo, J., ¨nen, Oncogene slr R. ¨ssler, e.Cell Dev. 20) h r6GFGP0/RG euae elahso by adhesion cell regulates GEP100/BRAG2 GEF Arf6 The (2006). 21 a.Cl Biol. Cell Nat. n.J Oncol. J. Int. Commun. Res. Biophys. Biochem. 16 178-181. , pe,H,Yn .K,Goio,S n tr,P. Storz, and S. Goodison, K., I. Yan, H., ppler, ¨ 127 2458-2469. , 193 20) nern:bdrcinl lotrcsgaigmachines. signaling allosteric bidirectional, Integrins: (2002). a.Rv o.Cl Biol. Cell Mol. Rev. Nat. 2433-2447. , .Cl Biol. Cell J. 61-70. , r .Cancer J. Br. 27 21) nernahso n oc opigaeindependently are coupling force and adhesion Integrin (2011). 31 Pathology ur pn Neurobiol. Opin. Curr. aeJ il Med. Biol. J. Yale .Cl Biol. Cell J. 249-262. , 3597-3606. , ratCne Res. Cancer Breast 20 a.Cl Biol. 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Curr. 20) h nqeNtriu fR- of N-terminus unique The (2005). 307 179-185. , 20) ansigatndynamics actin Harnessing (2006). R13. , MOJ. EMBO 19) irtbl agtn of targeting Microtubule (1999). 20) euaino substrate of Regulation (2002). 254-260. , 20) ncdw fRAB25 of Knockdown (2006). 19) a1 ndslsaof dysplasia in Rab11 (1999). 206 sebre,G,Muh C., Mauch, G., rstenberger, ¨ m .Pathol. J. Am. 21) nern rfi rapidly traffic Integrins (2011). 307-328. , 16 27 21) nRA screen RNAi An (2014). 315-320. , 30 185-211. , g,A,Ege,H., Edgren, A., ¨gi, hnhaZogLiu Zhong Zhonghua 20) Microtubule- (2005). 4539-4553. , 21) RCP-driven (2013). 7 404-414. , .Cl Biol. Cell J. .Neurosci. J. 20) Protein (2009). 167 34 243-253. , 746-761. , (2014). (2003). (2009). 146 Mol. Cell 32 , , otga,G,Ma-ei,V,Iodle . atoCsr,A,Fac,M., Franco, A., Castro-Castro, M., Irondelle, V., Meas-Yedid, G., Montagnac, aasi . amn,G,Bneiz . ag . hn,F,Skri A., Sakurai, F., Zhang, Z., Tang, K., Bennewitz, G., Carmona, Y., Manavski, M., T. 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