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W2146710073 abstract "Tetraspanins serve as molecular organizers of multiprotein microdomains in cell membranes. Hence to understand functions of tetraspanin proteins, it is critical to identify laterally interacting partner proteins. Here we used a novel technical approach involving exposure and cross-linking of membrane-proximal cysteines coupled with LC-MS/MS protein identification. In this manner we identified nine potential tetraspanin CD9 partners, including claudin-1. Chemical cross-linking yielded a CD9-claudin-1 heterodimer, thus confirming direct association and adding claudin-1 to the short list of proteins that can directly associate with CD9. Interaction of CD9 (and other tetraspanins) with claudin-1 was supported by subcellular colocalization and was confirmed in multiple cell lines, although other claudins (claudin-2, -3, -4, -5, and -7) associated to a much lesser extent. Moreover claudin-1 was distributed very similarly to CD9 in sucrose gradients and, like CD9, was released from A431 and A549 cells upon cholesterol depletion. These biochemical features of claudin-1 are characteristic of tetraspanin microdomain proteins. Although claudins are major structural components of intercellular tight junctions, CD9-claudin-1 complexes did not reside in tight junctions, and depletion of key tetraspanins (CD9 and CD151) by small interfering RNA had no effect on paracellular permeability. However, tetraspanin depletion did cause a marked decrease in the stability of newly synthesized claudin-1. In conclusion, these results (a) validate a technical approach that appears to be particularly well suited for identifying protein partners directly associated with tetraspanins or with other proteins that contain membrane-proximal cysteines and (b) provide insight into how non-junctional claudins may be regulated in the context of tetraspanin-enriched microdomains. Tetraspanins serve as molecular organizers of multiprotein microdomains in cell membranes. Hence to understand functions of tetraspanin proteins, it is critical to identify laterally interacting partner proteins. Here we used a novel technical approach involving exposure and cross-linking of membrane-proximal cysteines coupled with LC-MS/MS protein identification. In this manner we identified nine potential tetraspanin CD9 partners, including claudin-1. Chemical cross-linking yielded a CD9-claudin-1 heterodimer, thus confirming direct association and adding claudin-1 to the short list of proteins that can directly associate with CD9. Interaction of CD9 (and other tetraspanins) with claudin-1 was supported by subcellular colocalization and was confirmed in multiple cell lines, although other claudins (claudin-2, -3, -4, -5, and -7) associated to a much lesser extent. Moreover claudin-1 was distributed very similarly to CD9 in sucrose gradients and, like CD9, was released from A431 and A549 cells upon cholesterol depletion. These biochemical features of claudin-1 are characteristic of tetraspanin microdomain proteins. Although claudins are major structural components of intercellular tight junctions, CD9-claudin-1 complexes did not reside in tight junctions, and depletion of key tetraspanins (CD9 and CD151) by small interfering RNA had no effect on paracellular permeability. However, tetraspanin depletion did cause a marked decrease in the stability of newly synthesized claudin-1. In conclusion, these results (a) validate a technical approach that appears to be particularly well suited for identifying protein partners directly associated with tetraspanins or with other proteins that contain membrane-proximal cysteines and (b) provide insight into how non-junctional claudins may be regulated in the context of tetraspanin-enriched microdomains. Tetraspanin proteins regulate cell fusion, invasion, migration, and differentiation thereby affecting a variety of physiological processes in the brain, eye, skin, immune system, developing embryo, blood vessels, tumor cells, and elsewhere (1Boucheix C. Rubinstein E. Tetraspanins.Cell. Mol. Life Sci. 2001; 58: 1189-1205Crossref PubMed Scopus (533) Google Scholar, 2Wright M.D. Moseley G.W. van Spriel A.B. Tetraspanin microdomains in immune cell signalling and malignant disease.Tissue Antigens. 2004; 64: 533-542Crossref PubMed Scopus (127) Google Scholar, 3Levy S. Shoham T. The tetraspanin web modulates immune-signalling complexes.Nat. Rev. Immunol. 2005; 5: 136-148Crossref PubMed Scopus (478) Google Scholar, 4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 5Hemler M.E. Tetraspanin functions and associated microdomains.Nat. Rev. Mol. Cell Biol. 2005; 6: 801-811Crossref PubMed Scopus (987) Google Scholar). Genetic evidence points to critical roles for tetraspanins in mammals, insects, worms, and fungi (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 6Stein K.K. Primakoff P. Myles D. Sperm-egg fusion: events at the plasma membrane.J. Cell Sci. 2004; 117: 6269-6274Crossref PubMed Scopus (86) Google Scholar, 7Fradkin L.G. Kamphorst J.T. DiAntonio A. Goodman C.S. Noordermeer J.N. Genomewide analysis of the Drosophila tetraspanins reveals a subset with similar function in the formation of the embryonic synapse.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13663-13668Crossref PubMed Scopus (60) Google Scholar, 8Xu H. Lee S.J. Suzuki E. Dugan K.D. Stoddard A. Li H.S. Chodosh L.A. Montell C. A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen.EMBO J. 2004; 23: 811-822Crossref PubMed Scopus (95) Google Scholar, 9Sinenko S.A. Mathey-Prevot B. Increased expression of Drosophila tetraspanin, Tsp68C, suppresses the abnormal proliferation of ytr-deficient and Ras/Raf-activated hemocytes.Oncogene. 2004; 23: 9120-9128Crossref PubMed Scopus (94) Google Scholar, 10Moribe H. Yochem J. Yamada H. Tabuse Y. Fujimoto T. Mekada E. Tetraspanin protein (TSP-15) is required for epidermal integrity in Caenorhabditis elegans.J. Cell Sci. 2004; 117: 5209-5220Crossref PubMed Scopus (71) Google Scholar, 11Gourgues M. Clergeot P.H. Veneault C. Cots J. Sibuet S. Brunet-Simon A. Levis C. Langin T. Lebrun M.H. A new class of tetraspanins in fungi.Biochem. Biophys. Res. Commun. 2002; 297: 1197-1204Crossref PubMed Scopus (33) Google Scholar). Although tetraspanins are transmembrane proteins that typically reside on the cell surface, they do not generally function as ligands or receptors. Rather they assemble with themselves and other proteins, together with gangliosides and cholesterol, to form tetraspanin-enriched microdomains (TEMs) 1The abbreviations used are: TEM, tetraspanin-enriched microdomain; EWI, protein family with conserved Glu-Trp-Ile motif; 2-BP, 2-bromopalmitate; DTME, dithiobismaleimidoethane; MβCD, methyl-β-cyclodextrin; TJ, tight junction; siRNA, small interfering RNA; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF; MDCK, Madin-Darby canine kidney; DMEM, Dulbecco's modified Eagle's medium; mAb, monoclonal antibody; MHC, major histocompatibility complex; IP, immunoprecipitation; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition. 1The abbreviations used are: TEM, tetraspanin-enriched microdomain; EWI, protein family with conserved Glu-Trp-Ile motif; 2-BP, 2-bromopalmitate; DTME, dithiobismaleimidoethane; MβCD, methyl-β-cyclodextrin; TJ, tight junction; siRNA, small interfering RNA; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF; MDCK, Madin-Darby canine kidney; DMEM, Dulbecco's modified Eagle's medium; mAb, monoclonal antibody; MHC, major histocompatibility complex; IP, immunoprecipitation; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition. (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 5Hemler M.E. Tetraspanin functions and associated microdomains.Nat. Rev. Mol. Cell Biol. 2005; 6: 801-811Crossref PubMed Scopus (987) Google Scholar, 12Nydegger S. Khurana S. Krementsov D.N. Foti M. Thali M. Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1.J. Cell Biol. 2006; 173: 795-807Crossref PubMed Scopus (189) Google Scholar, 13Odintsova E. Butters T.D. Monti E. Sprong H. van Meer G. Berditchevski F. Gangliosides play an important role in the organisation of CD82-enriched microdomains.Biochem. J. 2006; 400: 315-325Crossref PubMed Scopus (69) Google Scholar). Hence to understand how tetraspanin proteins function, it is necessary to identify their partner proteins. Partner proteins for tetraspanins include integrins, Ig superfamily proteins, growth factors and their receptors, G-protein coupled receptors, signaling enzymes, and various other molecules (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 14Tarrant J.M. Robb L. van Spriel A.B. Wright M.D. Tetraspanins: molecular organisers of the leukocyte surface.Trends Immunol. 2003; 24: 610-617Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 15Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye.J. Cell Sci. 2001; 114: 4143-4151Crossref PubMed Google Scholar, 16Deng J. Yeung V.P. Tsitoura D. DeKruyff R.H. Umetsu D.T. Levy S. Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice.J. Immunol. 2000; 165: 5054-5061Crossref PubMed Scopus (47) Google Scholar). However, for many of the 33 mammalian tetraspanins, no partner proteins have been yet identified. A recent strategy for discovering partner proteins has been to lyse cells in relatively mild detergent (e.g. Brij 96/97), collect tetraspanin complexes, fractionate tetraspanin-associated proteins by SDS-PAGE, and then to identify them using nanoscale LC-MS/MS (17Stipp C.S. Orlicky D. Hemler M.E. FPRP, a major, highly stoichiometric, highly specific CD81 and CD9-associated protein.J. Biol. Chem. 2001; 276: 4853-4862Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 18Stipp C.S. Kolesnikova T.V. Hemler M.E. EWI-2 is a major CD9 and CD81 partner, and member of a novel Ig protein subfamily.J. Biol. Chem. 2001; 276: 40545-40554Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 19Little K.D. Hemler M.E. Stipp C.S. Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Gαq/11 association.Mol. Biol. Cell. 2004; 15: 2375-2387Crossref PubMed Scopus (165) Google Scholar, 20Le Naour F. Andre M. Greco C. Billard M. Sordat B. Emile J.F. Lanza F. Boucheix C. Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells.Mol. Cell. Proteomics. 2006; 5: 845-857Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Although this approach can be quite effective, the use of mild detergents increases the number of nonspecific and indirectly associated proteins that are identified.Covalent chemical cross-linking has been a useful tool for demonstrating direct tetraspanin protein-protein interactions. For example, it has been used to demonstrate direct associations of tetraspanins UP1a, UP1b, CD151, CD9, and CD81 with respective partner proteins UPII, UPIII, α3β1 integrin, EWI-F, and EWI-2 (18Stipp C.S. Kolesnikova T.V. Hemler M.E. EWI-2 is a major CD9 and CD81 partner, and member of a novel Ig protein subfamily.J. Biol. Chem. 2001; 276: 40545-40554Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 21Wu X.-R. Medina J.J. Sun T.-T. Selective interactions of UPIa and UPIb, two members of the transmembrane 4 superfamily, with distinct single transmembrane-domained proteins in differentiated urothelial cells.J. Biol. Chem. 1995; 270: 29752-29759Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 22Yauch R.L. Kazarov A.R. Desai B. Lee R.T. Hemler M.E. Direct extracellular contact between integrin α3β1 and TM4SF protein CD151.J. Biol. Chem. 2000; 275: 9230-9238Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 23Charrin S. Le Naour F. Oualid M. Billard M. Faure G. Hanash S.M. Boucheix C. Rubinstein E. The major CD9 and CD81 molecular partner. Identification and characterization of the complexes.J. Biol. Chem. 2001; 276: 14329-14337Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). For CD9 and other tetraspanin proteins, inhibition of protein palmitoylation leads to exposure of membrane-proximal cysteines, which then can be cross-linked (24Kovalenko O.V. Yang X. Kolesnikova T.V. Hemler M.E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking.Biochem. J. 2004; 377: 407-417Crossref PubMed Scopus (108) Google Scholar). In this manner, CD9 was shown to form homodimers, -trimers, and -tetramers (24Kovalenko O.V. Yang X. Kolesnikova T.V. Hemler M.E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking.Biochem. J. 2004; 377: 407-417Crossref PubMed Scopus (108) Google Scholar, 25Kovalenko O.V. Metcalf D.G. DeGrado W.F. Hemler M.E. Structural organization and interactions of transmembrane domains in tetraspanin proteins.BMC Struct. Biol. 2005; 5: 11Crossref PubMed Scopus (82) Google Scholar, 26Yang X.H. Kovalenko O.V. Kolesnikova T.V. Andzelm M.M. Rubinstein E. Strominger J.L. Hemler M.E. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization.J. Biol. Chem. 2006; 281: 12976-12985Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Nearly all tetraspanins undergo palmitoylation and contain multiple intracellular cysteine palmitoylation sites with proximity to transmembrane domains 1, 2, 3, and/or 4 (27Yang X. Claas C. Kraeft S.K. Chen L.B. Wang Z. Kreidberg J.A. Hemler M.E. Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.Mol. Biol. Cell. 2002; 13: 767-781Crossref PubMed Scopus (189) Google Scholar, 28Berditchevski F. Odintsova E. Sawada S. Gilbert E. Expression of the palmitoylation-deficient CD151 weakens the association of α3β1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling.J. Biol. Chem. 2002; 277: 36991-37000Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 29Charrin S. Manie S. Oualid M. Billard M. Boucheix C. Rubinstein E. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation.FEBS Lett. 2002; 516: 139-144Crossref PubMed Scopus (172) Google Scholar, 30Zhou B. Liu L. Reddivari M. Zhang X.A. The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity.Cancer Res. 2004; 64: 7455-7463Crossref PubMed Scopus (81) Google Scholar). Furthermore many tetraspanin partner proteins are also palmitoylated. For example CD9 partners (CD36, α3 and α6 integrins, EWI-2, and EWI-F) all contain membrane-proximal cysteines and are known to undergo palmitoylation (31Tao N. Wagner S.J. Lublin D.M. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.J. Biol. Chem. 1996; 271: 22315-22320Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 32Yang X. Kovalenko O.V. Tang W. Claas C. Stipp C.S. Hemler M.E. Palmitoylation supports assembly and function of integrin-tetraspanin complexes.J. Cell Biol. 2004; 167: 1231-1240Crossref PubMed Scopus (164) Google Scholar). 2O. V. Kovalenko, T. V. Kolesnikova, X. H. Yang, and M. E. Hemler, unpublished observations. 2O. V. Kovalenko, T. V. Kolesnikova, X. H. Yang, and M. E. Hemler, unpublished observations. Palmitoylation of tetraspanins and their partners helps to stabilize tetraspanin-enriched microdomains (27Yang X. Claas C. Kraeft S.K. Chen L.B. Wang Z. Kreidberg J.A. Hemler M.E. Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.Mol. Biol. Cell. 2002; 13: 767-781Crossref PubMed Scopus (189) Google Scholar, 28Berditchevski F. Odintsova E. Sawada S. Gilbert E. Expression of the palmitoylation-deficient CD151 weakens the association of α3β1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling.J. Biol. Chem. 2002; 277: 36991-37000Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 29Charrin S. Manie S. Oualid M. Billard M. Boucheix C. Rubinstein E. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation.FEBS Lett. 2002; 516: 139-144Crossref PubMed Scopus (172) Google Scholar, 32Yang X. Kovalenko O.V. Tang W. Claas C. Stipp C.S. Hemler M.E. Palmitoylation supports assembly and function of integrin-tetraspanin complexes.J. Cell Biol. 2004; 167: 1231-1240Crossref PubMed Scopus (164) Google Scholar). To identify more efficiently the proteins that directly associate with tetraspanins, we developed a novel strategy that involves (i) partial inhibition of protein palmitoylation to expose membrane-proximal cysteines, (ii) covalent cross-linking of exposed cysteines, (iii) cell lysis and immunoisolation of tetraspanin complexes, and (iv) protein identification by LC-MS/MS. Using this approach, we discovered a direct protein-protein interaction between tetraspanin CD9 and claudin-1.Tetraspanin CD9 plays a major role during sperm-egg fusion (33Miyado K. Yamada G. Yamada S. Hasuwa H. Nakamura Y. Ryu F. Suzuki K. Kosai K. Inoue K. Ogura A. Okabe M. Mekada E. Requirement of CD9 on the egg plasma membrane for fertilization.Science. 2000; 287: 321-324Crossref PubMed Scopus (553) Google Scholar, 34Le Naour F. Rubinstein E. Jasmin C. Prenant M. Boucheix C. Severely reduced female fertility in CD9-deficient mice.Science. 2000; 287: 319-321Crossref PubMed Scopus (533) Google Scholar, 35Kaji K. Oda S. Shikano T. Ohnuki T. Uematsu Y. Sakagami J. Tada N. Miyazaki S. Kudo A. The gamete fusion process is defective in eggs of Cd9-deficient mice.Nat. Genet. 2000; 24: 279-282Crossref PubMed Scopus (384) Google Scholar), other types of cell-cell fusion (36Tachibana I. Hemler M.E. Role of transmembrane-4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance.J. Cell Biol. 1999; 146: 893-904Crossref PubMed Scopus (203) Google Scholar, 37Takeda Y. Tachibana I. Miyado K. Kobayashi M. Miyazaki T. Funakoshi T. Kimura H. Yamane H. Saito Y. Goto H. Yoneda T. Yoshida M. Kumagai T. Osaki T. Hayashi S. Kawase I. Mekada E. Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes.J. Cell Biol. 2003; 161: 945-956Crossref PubMed Scopus (142) Google Scholar, 38Willett B. Hosie M. Shaw A. Neil J. Inhibition of feline immunodeficiency virus infection by CD9 antibody operates after virus entry and is independent of virus tropism.J. Gen. Virol. 1997; 78: 611-618Crossref PubMed Scopus (39) Google Scholar, 39Fukudome K. Furuse M. Imai T. Nishimura M. Takagi S. Hinuma Y. Yoshie O. Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV-1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive T cells.J. Virol. 1992; 66: 1394-1401Crossref PubMed Google Scholar), cell migration, and tumor suppression (40Ikeyama S. Koyama M. Yamaoko M. Sasada R. Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA.J. Exp. Med. 1993; 177: 1231-1237Crossref PubMed Scopus (274) Google Scholar, 41Miyake M. Inufusa H. Adachi M. Ishida H. Hashida H. Tokuhara T. Kakehi Y. Suppression of pulmonary metastasis using adenovirally motility related protein-1 (MRP-1/CD9) gene delivery.Oncogene. 2000; 19: 5221-5226Crossref PubMed Scopus (47) Google Scholar). It also affects paranodal junction formation in the peripheral nervous system (42Ishibashi T. Ding L. Ikenaka K. Inoue Y. Miyado K. Mekada E. Baba H. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation.J. Neurosci. 2004; 24: 96-102Crossref PubMed Scopus (63) Google Scholar) and signaling by membrane-bound agonists for the epidermal growth factor (EGF) receptor (43Shi W. Fan H. Shum L. Derynck R. The tetraspanin CD9 associates with transmembrane TGF-α and regulates TGF-α-induced EGF receptor activation and cell proliferation.J. Cell Biol. 2000; 148: 591-602Crossref PubMed Scopus (144) Google Scholar, 44Higashiyama S. Iwamoto R. Goishi K. Raab G. Taniguchi N. Klagsbrun M. Mekada E. The membrane protein CD9/DRAP27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor.J. Cell Biol. 1995; 128: 929-938Crossref PubMed Scopus (279) Google Scholar, 45Inui S. Higashiyama S. Hashimoto K. Higashiyama M. Yoshikawa K. Taniguchi N. Possible role of coexpression of CD9 with membrane-anchored heparin-binding EGF-like growth factor and amphiregulin in cultured human keratinocyte growth.J. Cell Physiol. 1997; 171: 291-298Crossref PubMed Scopus (68) Google Scholar). In this regard, CD9 not only associates directly with Ig superfamily proteins (EWI-2 and EWI-F) but also may directly contact membrane-bound growth factor HB-EGF (46Iwamoto R. Higashiyama S. Mitamura T. Taniguchi N. Klagsbrun M. Mekada E. Heparin-binding EGF-like growth factor, which acts as a diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which upregulates functional receptors and diphtheria toxin sensitivity.EMBO J. 1994; 13: 2322-2330Crossref PubMed Scopus (239) Google Scholar). Several new CD9 partners have been identified recently (20Le Naour F. Andre M. Greco C. Billard M. Sordat B. Emile J.F. Lanza F. Boucheix C. Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells.Mol. Cell. Proteomics. 2006; 5: 845-857Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar) but were not shown to associate directly. Like tetraspanins, claudins also contain four transmembrane domains, but the sequences and functions of these two families of proteins are quite distinct. Claudins, including claudin-1, are key components of epithelial and endothelial tight junctions (TJs), which act as a barrier to paracellular flux of water and solutes and transmigration of other cells (47Turksen K. Troy T.C. Barriers built on claudins.J. Cell Sci. 2004; 117: 2435-2447Crossref PubMed Scopus (341) Google Scholar, 48Tsukita S. Furuse M. Itoh M. Multifunctional strands in tight junctions.Nat. Rev. Mol. Cell Biol. 2001; 2: 285-293Crossref PubMed Scopus (1995) Google Scholar). Within tight junctions, claudins on apposing cells form homophilic and heterophilic complexes (49Furuse M. Sasaki H. Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands.J. Cell Biol. 1999; 147: 891-903Crossref PubMed Scopus (609) Google Scholar). Claudins also associate with other TJ proteins, including occludin and ZO-1 (50Heiskala M. Peterson P.A. Yang Y. The roles of claudin superfamily proteins in paracellular transport.Traffic. 2001; 2: 93-98Crossref PubMed Scopus (209) Google Scholar). Like tetraspanins, claudins possess juxtamembrane cysteine residues, and claudin-14 was shown to undergo palmitoylation, which is required for proper TJ localization and barrier function (51Van Itallie C.M. Gambling T.M. Carson J.L. Anderson J.M. Palmitoylation of claudins is required for efficient tight-junction localization.J. Cell Sci. 2005; 118: 1427-1436Crossref PubMed Scopus (141) Google Scholar). In this study, we demonstrate that tetraspanins (such as CD9) can associate with and stabilize the expression of claudins when they are not in tight junctions. Tetraspanin proteins regulate cell fusion, invasion, migration, and differentiation thereby affecting a variety of physiological processes in the brain, eye, skin, immune system, developing embryo, blood vessels, tumor cells, and elsewhere (1Boucheix C. Rubinstein E. Tetraspanins.Cell. Mol. Life Sci. 2001; 58: 1189-1205Crossref PubMed Scopus (533) Google Scholar, 2Wright M.D. Moseley G.W. van Spriel A.B. Tetraspanin microdomains in immune cell signalling and malignant disease.Tissue Antigens. 2004; 64: 533-542Crossref PubMed Scopus (127) Google Scholar, 3Levy S. Shoham T. The tetraspanin web modulates immune-signalling complexes.Nat. Rev. Immunol. 2005; 5: 136-148Crossref PubMed Scopus (478) Google Scholar, 4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 5Hemler M.E. Tetraspanin functions and associated microdomains.Nat. Rev. Mol. Cell Biol. 2005; 6: 801-811Crossref PubMed Scopus (987) Google Scholar). Genetic evidence points to critical roles for tetraspanins in mammals, insects, worms, and fungi (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 6Stein K.K. Primakoff P. Myles D. Sperm-egg fusion: events at the plasma membrane.J. Cell Sci. 2004; 117: 6269-6274Crossref PubMed Scopus (86) Google Scholar, 7Fradkin L.G. Kamphorst J.T. DiAntonio A. Goodman C.S. Noordermeer J.N. Genomewide analysis of the Drosophila tetraspanins reveals a subset with similar function in the formation of the embryonic synapse.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13663-13668Crossref PubMed Scopus (60) Google Scholar, 8Xu H. Lee S.J. Suzuki E. Dugan K.D. Stoddard A. Li H.S. Chodosh L.A. Montell C. A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen.EMBO J. 2004; 23: 811-822Crossref PubMed Scopus (95) Google Scholar, 9Sinenko S.A. Mathey-Prevot B. Increased expression of Drosophila tetraspanin, Tsp68C, suppresses the abnormal proliferation of ytr-deficient and Ras/Raf-activated hemocytes.Oncogene. 2004; 23: 9120-9128Crossref PubMed Scopus (94) Google Scholar, 10Moribe H. Yochem J. Yamada H. Tabuse Y. Fujimoto T. Mekada E. Tetraspanin protein (TSP-15) is required for epidermal integrity in Caenorhabditis elegans.J. Cell Sci. 2004; 117: 5209-5220Crossref PubMed Scopus (71) Google Scholar, 11Gourgues M. Clergeot P.H. Veneault C. Cots J. Sibuet S. Brunet-Simon A. Levis C. Langin T. Lebrun M.H. A new class of tetraspanins in fungi.Biochem. Biophys. Res. Commun. 2002; 297: 1197-1204Crossref PubMed Scopus (33) Google Scholar). Although tetraspanins are transmembrane proteins that typically reside on the cell surface, they do not generally function as ligands or receptors. Rather they assemble with themselves and other proteins, together with gangliosides and cholesterol, to form tetraspanin-enriched microdomains (TEMs) 1The abbreviations used are: TEM, tetraspanin-enriched microdomain; EWI, protein family with conserved Glu-Trp-Ile motif; 2-BP, 2-bromopalmitate; DTME, dithiobismaleimidoethane; MβCD, methyl-β-cyclodextrin; TJ, tight junction; siRNA, small interfering RNA; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF; MDCK, Madin-Darby canine kidney; DMEM, Dulbecco's modified Eagle's medium; mAb, monoclonal antibody; MHC, major histocompatibility complex; IP, immunoprecipitation; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition. 1The abbreviations used are: TEM, tetraspanin-enriched microdomain; EWI, protein family with conserved Glu-Trp-Ile motif; 2-BP, 2-bromopalmitate; DTME, dithiobismaleimidoethane; MβCD, methyl-β-cyclodextrin; TJ, tight junction; siRNA, small interfering RNA; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF; MDCK, Madin-Darby canine kidney; DMEM, Dulbecco's modified Eagle's medium; mAb, monoclonal antibody; MHC, major histocompatibility complex; IP, immunoprecipitation; TGF, transforming growth factor; EMT, epithelial-mesenchymal transition. (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 5Hemler M.E. Tetraspanin functions and associated microdomains.Nat. Rev. Mol. Cell Biol. 2005; 6: 801-811Crossref PubMed Scopus (987) Google Scholar, 12Nydegger S. Khurana S. Krementsov D.N. Foti M. Thali M. Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1.J. Cell Biol. 2006; 173: 795-807Crossref PubMed Scopus (189) Google Scholar, 13Odintsova E. Butters T.D. Monti E. Sprong H. van Meer G. Berditchevski F. Gangliosides play an important role in the organisation of CD82-enriched microdomains.Biochem. J. 2006; 400: 315-325Crossref PubMed Scopus (69) Google Scholar). Hence to understand how tetraspanin proteins function, it is necessary to identify their partner proteins. Partner proteins for tetraspanins include integrins, Ig superfamily proteins, growth factors and their receptors, G-protein coupled receptors, signaling enzymes, and various other molecules (4Hemler M.E. Tetraspanin proteins mediate cellular penetration, invasion and fusion events, and define a novel type of membrane microdomain.Annu. Rev. Cell Dev. Biol. 2003; 19: 397-422Crossref PubMed Scopus (638) Google Scholar, 14Tarrant J.M. Robb L. van Spriel A.B. Wright M.D. Tetraspanins: molecular organisers of the leukocyte surface.Trends Immunol. 2003; 24: 610-617Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 15Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye.J. Cell Sci. 2001; 114: 4143-4151Crossref PubMed Google Scholar, 16Deng J. Yeung V.P. Tsitoura D. DeKruyff R.H. Umetsu D.T. Levy S. Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice.J. Immunol. 2000; 165: 5054-5061Crossref PubMed Scopus (47) Google Scholar). However, for many of the 33 mammalian tetraspanins, no partner proteins have been yet identified. A recent strategy for discovering partner proteins has been to lyse cells in relatively mild detergent (e.g. Brij 96/97), collect tetraspanin complexes, fractionate tetraspanin-associated proteins by SDS-PAGE, and then to identify them using nanoscale LC-MS/MS (17Stipp C.S. Orlicky D. Hemler M.E. FPRP, a major, highly stoichiometric, highly specific CD81 and CD9-associated protein.J. Biol. Chem. 2001; 276: 4853-4862Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 18Stipp C.S. Kolesnikova T.V. Hemler M.E. EWI-2 is a major CD9 and CD81 partner, and member of a novel Ig protein subfamily.J. Biol. Chem. 2001; 276: 40545-40554Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 19Little K.D. Hemler M.E. Stipp C.S. Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Gαq/11 association.Mol. Biol. Cell. 2004; 15: 2375-2387Crossref PubMed Scopus (165) Google Scholar, 20Le Naour F. Andre M. Greco C. Billard M. Sordat B. Emile J.F. Lanza F. Boucheix C. Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells.Mol. Cell. Proteomics. 2006; 5: 845-857Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Although this approach can be quite effective, the use of mild detergents increases the number of nonspecific and indirectly associated proteins that are identified. Covalent chemical cross-linking has been a useful tool for demonstrating direct tetraspanin protein-protein interactions. For example, it has been used to demonstrate direct associations of tetraspanins UP1a, UP1b, CD151, CD9, and CD81 with respective partner proteins UPII, UPIII, α3β1 integrin, EWI-F, and EWI-2 (18Stipp C.S. Kolesnikova T.V. Hemler M.E. EWI-2 is a major CD9 and CD81 partner, and member of a novel Ig protein subfamily.J. Biol. Chem. 2001; 276: 40545-40554Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 21Wu X.-R. Medina J.J. Sun T.-T. Selective interactions of UPIa and UPIb, two members of the transmembrane 4 superfamily, with distinct single transmembrane-domained proteins in differentiated urothelial cells.J. Biol. Chem. 1995; 270: 29752-29759Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 22Yauch R.L. Kazarov A.R. Desai B. Lee R.T. Hemler M.E. Direct extracellular contact between integrin α3β1 and TM4SF protein CD151.J. Biol. Chem. 2000; 275: 9230-9238Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 23Charrin S. Le Naour F. Oualid M. Billard M. Faure G. Hanash S.M. Boucheix C. Rubinstein E. The major CD9 and CD81 molecular partner. Identification and characterization of the complexes.J. Biol. Chem. 2001; 276: 14329-14337Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). For CD9 and other tetraspanin proteins, inhibition of protein palmitoylation leads to exposure of membrane-proximal cysteines, which then can be cross-linked (24Kovalenko O.V. Yang X. Kolesnikova T.V. Hemler M.E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking.Biochem. J. 2004; 377: 407-417Crossref PubMed Scopus (108) Google Scholar). In this manner, CD9 was shown to form homodimers, -trimers, and -tetramers (24Kovalenko O.V. Yang X. Kolesnikova T.V. Hemler M.E. Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking.Biochem. J. 2004; 377: 407-417Crossref PubMed Scopus (108) Google Scholar, 25Kovalenko O.V. Metcalf D.G. DeGrado W.F. Hemler M.E. Structural organization and interactions of transmembrane domains in tetraspanin proteins.BMC Struct. Biol. 2005; 5: 11Crossref PubMed Scopus (82) Google Scholar, 26Yang X.H. Kovalenko O.V. Kolesnikova T.V. Andzelm M.M. Rubinstein E. Strominger J.L. Hemler M.E. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization.J. Biol. Chem. 2006; 281: 12976-12985Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Nearly all tetraspanins undergo palmitoylation and contain multiple intracellular cysteine palmitoylation sites with proximity to transmembrane domains 1, 2, 3, and/or 4 (27Yang X. Claas C. Kraeft S.K. Chen L.B. Wang Z. Kreidberg J.A. Hemler M.E. Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.Mol. Biol. Cell. 2002; 13: 767-781Crossref PubMed Scopus (189) Google Scholar, 28Berditchevski F. Odintsova E. Sawada S. Gilbert E. Expression of the palmitoylation-deficient CD151 weakens the association of α3β1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling.J. Biol. Chem. 2002; 277: 36991-37000Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 29Charrin S. Manie S. Oualid M. Billard M. Boucheix C. Rubinstein E. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation.FEBS Lett. 2002; 516: 139-144Crossref PubMed Scopus (172) Google Scholar, 30Zhou B. Liu L. Reddivari M. Zhang X.A. The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity.Cancer Res. 2004; 64: 7455-7463Crossref PubMed Scopus (81) Google Scholar). Furthermore many tetraspanin partner proteins are also palmitoylated. For example CD9 partners (CD36, α3 and α6 integrins, EWI-2, and EWI-F) all contain membrane-proximal cysteines and are known to undergo palmitoylation (31Tao N. Wagner S.J. Lublin D.M. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.J. Biol. Chem. 1996; 271: 22315-22320Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 32Yang X. Kovalenko O.V. Tang W. Claas C. Stipp C.S. Hemler M.E. Palmitoylation supports assembly and function of integrin-tetraspanin complexes.J. Cell Biol. 2004; 167: 1231-1240Crossref PubMed Scopus (164) Google Scholar). 2O. V. Kovalenko, T. V. Kolesnikova, X. H. Yang, and M. E. Hemler, unpublished observations. 2O. V. Kovalenko, T. V. Kolesnikova, X. H. Yang, and M. E. Hemler, unpublished observations. Palmitoylation of tetraspanins and their partners helps to stabilize tetraspanin-enriched microdomains (27Yang X. Claas C. Kraeft S.K. Chen L.B. Wang Z. Kreidberg J.A. Hemler M.E. Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.Mol. Biol. 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To identify more efficiently the proteins that directly associate with tetraspanins, we developed a novel strategy that involves (i) partial inhibition of protein palmitoylation to expose membrane-proximal cysteines, (ii) covalent cross-linking of exposed cysteines, (iii) cell lysis and immunoisolation of tetraspanin complexes, and (iv) protein identification by LC-MS/MS. Using this approach, we discovered a direct protein-protein interaction between tetraspanin CD9 and claudin-1. Tetraspanin CD9 plays a major role during sperm-egg fusion (33Miyado K. Yamada G. Yamada S. Hasuwa H. Nakamura Y. Ryu F. Suzuki K. Kosai K. Inoue K. Ogura A. Okabe M. Mekada E. Requirement of CD9 on the egg plasma membrane for fertilization.Science. 2000; 287: 321-324Crossref PubMed Scopus (553) Google Scholar, 34Le Naour F. Rubinstein E. Jasmin C. Prenant M. Boucheix C. Severely reduced female fertility in CD9-deficient mice.Science. 2000; 287: 319-321Crossref PubMed Scopus (533) Google Scholar, 35Kaji K. 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Profiling of the tetraspanin web of human colon cancer cells.Mol. Cell. Proteomics. 2006; 5: 845-857Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar) but were not shown to associate directly. Like tetraspanins, claudins also contain four transmembrane domains, but the sequences and functions of these two families of proteins are quite distinct. Claudins, including claudin-1, are key components of epithelial and endothelial tight junctions (TJs), which act as a barrier to paracellular flux of water and solutes and transmigration of other cells (47Turksen K. Troy T.C. Barriers built on claudins.J. Cell Sci. 2004; 117: 2435-2447Crossref PubMed Scopus (341) Google Scholar, 48Tsukita S. Furuse M. Itoh M. Multifunctional strands in tight junctions.Nat. Rev. Mol. Cell Biol. 2001; 2: 285-293Crossref PubMed Scopus (1995) Google Scholar). Within tight junctions, claudins on apposing cells form homophilic and heterophilic complexes (49Furuse M. Sasaki H. Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands.J. Cell Biol. 1999; 147: 891-903Crossref PubMed Scopus (609) Google Scholar). Claudins also associate with other TJ proteins, including occludin and ZO-1 (50Heiskala M. Peterson P.A. Yang Y. The roles of claudin superfamily proteins in paracellular transport.Traffic. 2001; 2: 93-98Crossref PubMed Scopus (209) Google Scholar). Like tetraspanins, claudins possess juxtamembrane cysteine residues, and claudin-14 was shown to undergo palmitoylation, which is required for proper TJ localization and barrier function (51Van Itallie C.M. Gambling T.M. Carson J.L. Anderson J.M. Palmitoylation of claudins is required for efficient tight-junction localization.J. Cell Sci. 2005; 118: 1427-1436Crossref PubMed Scopus (141) Google Scholar). In this study, we demonstrate that tetraspanins (such as CD9) can associate with and stabilize the expression of claudins when they are not in tight junctions. 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W2146710073 created "2016-06-24" @default.
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W2146710073 date "2007-11-01" @default.
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W2146710073 title "A Novel Cysteine Cross-linking Method Reveals a Direct Association between Claudin-1 and Tetraspanin CD9" @default.
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