Tetraspanin CD151 Promotes Cell Migration by Regulating Integrin Trafficking

Regulation of cell migration is an important feature of tetraspanin CD151. Although it is well established that CD151 physically associates with integrins, the mechanism by which CD151 regulates integrin-dependent cell migration is basically unknown. Given the fact that CD151 is localized in both the plasma membrane and intracellular vesicles, we found that CD151 and its associated α3β1, α5β1, and α6β1 integrins undergo endocytosis and accumulate in the same intracellular vesicular compartments. CD151 contains a YRSL sequence, a YXXφ type of endocytosis/sorting motif, in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuated CD151 internalization. The loss of CD151 trafficking completely abrogated CD151-promoted cell migration on extracellular matrices such as laminin and diminished the internalization of its associated integrins, indicating a critical role for integrin trafficking in regulating cell motility. In conclusion, the YXXφ motif-mediated internalization of CD151 promotes integrin-dependent cell migration by modulating the endocytosis and/or vesicular trafficking of its associated integrins. Regulation of cell migration is an important feature of tetraspanin CD151. Although it is well established that CD151 physically associates with integrins, the mechanism by which CD151 regulates integrin-dependent cell migration is basically unknown. Given the fact that CD151 is localized in both the plasma membrane and intracellular vesicles, we found that CD151 and its associated α3β1, α5β1, and α6β1 integrins undergo endocytosis and accumulate in the same intracellular vesicular compartments. CD151 contains a YRSL sequence, a YXXφ type of endocytosis/sorting motif, in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuated CD151 internalization. The loss of CD151 trafficking completely abrogated CD151-promoted cell migration on extracellular matrices such as laminin and diminished the internalization of its associated integrins, indicating a critical role for integrin trafficking in regulating cell motility. In conclusion, the YXXφ motif-mediated internalization of CD151 promotes integrin-dependent cell migration by modulating the endocytosis and/or vesicular trafficking of its associated integrins. Tetraspanin CD151 is functionally linked to cancer metastasis, hemidesmosome formation, neurite outgrowth, and vascular morphogenesis (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar, 2Testa J.E. Kim P.C. Liu J.-M. Quiqley J.P. Cancer Res. 1999; 59: 3812-3820PubMed Google Scholar, 3Sterk L.M.T. Kim C.A.W. Oomen L.C.J.M. Calafat J. Janssen H. Sonnenberg A. J. Cell Biol. 2000; 149: 969-982Crossref PubMed Scopus (189) Google Scholar, 4Stipp C.S. Kim M.E. J. Cell Sci. 2000; 113: 1871-1882Crossref PubMed Google Scholar, 5Zhang X.A. Kim A.R. Yang X. Bontrager A.L. Stipp C.S. Hemler M.E. Mol. Biol. Cell. 2002; 13: 1-11Crossref PubMed Scopus (118) Google Scholar). Although the mechanism remains obscure, cell movement appears to be the common theme for many of these events. The regulatory role of CD151 in cell migration is supported by the knock-out studies in mice (6Wright M.D. Kim S.M. Fitter S. Moseley G.W. Lau L.M. Sheng K.C. Apostolopoulos V. Stanley E.G. Jackson D.E. Ashman L.K. Mol. Cell. Biol. 2004; 24: 5978-5988Crossref PubMed Scopus (150) Google Scholar, 7Takeda Y. Kim A.R. Butterfield C.E. Hopkins B.D. Benjamin L.E. Kaipainen A. Hemler M.E. Blood. 2007; 109: 1524-1532Crossref PubMed Scopus (135) Google Scholar) and knockdown experiments in vitro (8Winterwood N.E. Kim A. Meland M.N. Ashman L.K. Stipp C.S. Mol. Biol. Cell. 2006; 17: 2707-2721Crossref PubMed Scopus (113) Google Scholar). Also, the association of CD151 with integrins, especially the laminin (LN) 2The abbreviations used are: LN, laminin; FN, fibronectin; ECM, extracellular matrix; HMEC, human dermal microvascular endothelial cells; Ab, antibody; mAb, monoclonal antibody; pAb, polyclonal antibody; TEM, tetraspanin-enriched microdomain; PKC, protein kinase C; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; FITC, fluorescein isothiocyanate.2The abbreviations used are: LN, laminin; FN, fibronectin; ECM, extracellular matrix; HMEC, human dermal microvascular endothelial cells; Ab, antibody; mAb, monoclonal antibody; pAb, polyclonal antibody; TEM, tetraspanin-enriched microdomain; PKC, protein kinase C; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; FITC, fluorescein isothiocyanate.-binding integrins, stands out as a prominent feature (3Sterk L.M.T. Kim C.A.W. Oomen L.C.J.M. Calafat J. Janssen H. Sonnenberg A. J. Cell Biol. 2000; 149: 969-982Crossref PubMed Scopus (189) Google Scholar, 9Yauch R.L. Kim F. Harler M.B. Reichner J. Hemler M.E. Mol. Biol. Cell. 1998; 9: 2751-2765Crossref PubMed Scopus (267) Google Scholar, 10Fitter S. Kim P.M. Jolliffe C.N. Ashman L.K. Biochem. J. 1999; 338: 61-70Crossref PubMed Scopus (100) Google Scholar, 11Serru V. Kim F.L. Billard M. Azorsa D.O. Lanza F. Boucheix C. Rubinstein E. Biochem. J. 1999; 340: 103-117Crossref PubMed Scopus (202) Google Scholar). CD151 is expressed in a variety of tissues and is especially abundant in epithelia, endothelia, cardiac muscle, smooth muscle, and megakaryocytes (12Sincock P.M. Kim G. Ashman L.K. J. Histochem. Cytochem. 1997; 45: 515-525Crossref PubMed Scopus (172) Google Scholar). Notably, the tissue distribution of CD151 is similar to the distribution of LN-binding integrins such as α3β1, α6β1, α6β4, and α7β1 (13Sterk L.M. Kim C.A. van den Berg J.G. Claessen N. Weening J.J. Sonnenberg A. J. Cell Sci. 2002; 115: 1161-1173Crossref PubMed Google Scholar), which is consistent with its ability to associate with these integrins and with a likely concomitant function during development (14Kreidberg J.A. Kim M.J. Goldstein S.L. Rennke H. Shepherd K. Jones R.C. Jaenisch R. Development (Camb.). 1996; 122: 3537-3547Crossref PubMed Google Scholar, 15Karamatic Crew V. Kim N. Kagan A. Green C.A. Levene C. Flinter F. Brady R.L. Daniels G. Anstee D.J. Blood. 2004; 104: 2217-2223Crossref PubMed Scopus (211) Google Scholar). At the cellular level, CD151 is present on plasma membrane and in intracellular vesicles (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar). On the cell surface, CD151 is localized in the basolateral membrane in endothelial and epithelial cells (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar, 16Yanez-Mo M. Kim A. Cabanas C. Marazuela M. Tejedor R. Ursa M.A. Ashman L.K. de Landazuri M.O. Sanchez-Madrid F. J. Cell Biol. 1998; 141: 791-804Crossref PubMed Scopus (239) Google Scholar, 17Shigeta M. Kim N. Ozawa M. Gu J. Hasegawa H. Sekiguchi K. J. Cell Biol. 2003; 163: 165-176Crossref PubMed Scopus (105) Google Scholar), whereas CD151 in vesicles (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar). CD151 associates with LN-binding integrins, it is that CD151 regulates CD151 is for cell by LN-binding integrin α6β1 J. Kim A.R. H. Hemler M.E. Sci. S. A. 2003; PubMed Scopus Google Scholar). CD151 the of integrin by the of this integrin R. Kim N. S. Y. Y. M. J. Hasegawa H. Sekiguchi K. Sci. S. A. PubMed Scopus Google Scholar). CD151 is a of that epithelial cells to (3Sterk L.M.T. Kim C.A.W. Oomen L.C.J.M. Calafat J. Janssen H. Sonnenberg A. J. Cell Biol. 2000; 149: 969-982Crossref PubMed Scopus (189) Google Scholar). CD151 to integrin to H. Kim K. K. S. J. 1998; Google Scholar). CD151 a role in S. Kim P.M. Jolliffe C.N. Ashman L.K. Biochem. J. 1999; 338: 61-70Crossref PubMed Scopus (100) Google Scholar). CD151 promotes the of epithelial in a protein kinase and M. Kim N. Ozawa M. Gu J. Hasegawa H. Sekiguchi K. J. Cell Biol. 2003; 163: 165-176Crossref PubMed Scopus (105) Google Scholar). CD151 integrin to to a that PKC, and N. Kim Ashman L.K. S.M. J.A. J. Cell Biol. 2003; 163: PubMed Scopus Google Scholar). CD151 contains extracellular and cytoplasmic The extracellular is for the association with and integrins R.L. Kim A.R. Hemler M.E. J. Biol. 2000; PubMed Scopus Google Scholar, F. Kim E. Fitter S. Ashman J. Biol. PubMed Scopus Google Scholar). The CD151 C-terminal cytoplasmic a role in The of the CD151 C-terminal cytoplasmic markedly integrin cell and cellular morphogenesis X.A. Kim A.R. Yang X. Bontrager A.L. Stipp C.S. Hemler M.E. Mol. Biol. Cell. 2002; 13: 1-11Crossref PubMed Scopus (118) Google Scholar, J. Kim A.R. H. Hemler M.E. Sci. S. A. 2003; PubMed Scopus Google Scholar). In the C-terminal cytoplasmic of CD151 regulates S. Kim M. E. F. J. Biol. 2003; PubMed Scopus Google Scholar). the C-terminal integrin to J. Kim A.R. H. Hemler M.E. Sci. S. A. 2003; PubMed Scopus Google Scholar). of indicating an role of the C-terminal of it is the C-terminal these The C-terminal cytoplasmic of CD151 contains a YRSL that the of the motif, in which is and and the with a H. Kim J. M.C. H. S. A. PubMed Scopus Google Scholar, Kim L.M. Biochem. 2003; PubMed Scopus Google Scholar). The YXXφ in the cytoplasmic of by a of Kim L.M. Biochem. 2003; PubMed Scopus Google Scholar, Kim S.L. 2003; PubMed Scopus Google Scholar). to that the YRSL motif CD151 is for the of CD151 C-terminal cytoplasmic and regulates CD151 such as integrin-dependent cell and and cell the and in in with and dermal microvascular endothelial cells the for and and in CD151 type and the YRSL the a as in X.A. Kim A.R. Yang X. Bontrager A.L. Stipp C.S. Hemler M.E. Mol. Biol. Cell. 2002; 13: 1-11Crossref PubMed Scopus (118) Google Scholar). the CD151 by the and in the YRSL of type CD151 C-terminal cytoplasmic with The human type and CD151 the and The CD151 by cells with and with a of of and by cell The and the CD151 type and and monoclonal used in this human CD151 R.L. Kim F. Harler M.B. Reichner J. Hemler M.E. Mol. Biol. Cell. 1998; 9: 2751-2765Crossref PubMed Scopus (267) Google Scholar) and by K. Sekiguchi and M. of and integrin and a The polyclonal integrin cytoplasmic X.A. Kim A.L. Stipp C.S. G. Hemler M.E. Mol. Biol. Cell. PubMed Scopus Google Scholar) and integrin cytoplasmic X.A. Kim A.R. Yang X. Bontrager A.L. Stipp C.S. Hemler M.E. Mol. Biol. Cell. 2002; 13: 1-11Crossref PubMed Scopus (118) Google Scholar). human CD151 the protein human integrin and integrin and used in the human plasma and laminin cells with with PBS, with with for and with for cells with for and on and with for with for with for and with for by with a for the cells with the cells with and with human CD151 the cells with an and an the with Green FITC, and by the and of and in a to a of of the out as Kim S. L.K. X.A. J. Biol. PubMed Scopus Google Scholar). cells with and/or for In the cell with cell the by the with protein and to The with the in for by and to the with and by the with by internalization of CD151 and integrins with with CD151 and/or integrin for The by with The cells for internalization for for of as in the The that to the cell and by with the The of the cell The cells and with The of integrin and CD151 internalization the established Kim S. L.K. X.A. J. Biol. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, Kim M. J. in Cell 1998; Scholar, Kim A. M. J. in Cell Scholar, M. Kim G. E. J.R. R. J. 1999; PubMed Scopus Google Scholar). with the to the cell The for to of the cell The by with The cells for for the internalization and with a for on to cell the internalization of CD151 and its associated the and with PBS, the cells in for and CD151 as and the integrin CD151 by and by The integrin and CD151 by as Kim S. L.K. X.A. J. Biol. PubMed Scopus Google Scholar). internalization an with the of integrin that the of integrin integrin Cell cell migration as X.A. Kim Liu J. Biol. 2003; PubMed Scopus Google Scholar). cells with with PBS, and the of The of the with and with for The cell The of in the well and in the for cells that and cells that to the of the and with The cells that the experiments and cells in the by the with The cells with PBS, and the with the the and The YRSL in CD151 the YRSL of CD151 is in regulating its intracellular trafficking and we this motif in human CD151 The and in CD151 YRSL motif with and the YRSL as the human CD151 and cells and established by and of by in CD151 and the expressed on the of cells cells in cells in the cell of CD151 on the that on the cells the the of CD151 in type and in the The of cell such as on and CD151 The cellular of CD151 CD151 type and the with a in the type of CD151 in the that in the The CD151 during cell The of the on CD151 the CD151 localized on the cell and in intracellular and (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar). Liu and X. A. CD151 the cell and the vesicular with CD151 that the YRSL motif is important for regulating CD151 In type we that of intracellular vesicles the internalization of CD151 in the and an a a of CD151 and in intracellular vesicles, whereas CD151 in this The the of CD151 endocytosis in the of the CD151 such as and the CD151 the cell a in the trafficking the YRSL motif is for CD151 CD151 Cell of cell is a prominent feature of CD151. CD151 internalization is important for cell the of on the with a of integrins, the integrin expressed in cells is the α6β1 integrin X.A. Kim A.R. Yang X. Bontrager A.L. Stipp C.S. Hemler M.E. Mol. Biol. Cell. 2002; 13: 1-11Crossref PubMed Scopus (118) Google Scholar), cell migration on is by integrin in the of CD151 in cell migration on both and consistent with (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar, 2Testa J.E. Kim P.C. Liu J.-M. Quiqley J.P. Cancer Res. 1999; 59: 3812-3820PubMed Google Scholar, 9Yauch R.L. Kim F. Harler M.B. Reichner J. Hemler M.E. Mol. Biol. Cell. 1998; 9: 2751-2765Crossref PubMed Scopus (267) Google Scholar, 16Yanez-Mo M. Kim A. Cabanas C. Marazuela M. Tejedor R. Ursa M.A. Ashman L.K. de Landazuri M.O. Sanchez-Madrid F. J. Cell Biol. 1998; 141: 791-804Crossref PubMed Scopus (239) Google Scholar). The ability of CD151 cells to and markedly with that of CD151 and The diminished cell migration of the that YRSL internalization is for CD151 of used to the of the on cell with the the cell migration CD151 whereas CD151 with the CD151 CD151 endocytosis an role in regulating integrin-dependent cell of CD151 the the loss of CD151 internalization cell we CD151 the the and CD151 of cells that integrins well with CD151 and the a a that the integrin the and the the and The protein and protein to the of the cell The of CD151 with CD151 that the in CD151 is CD151 these that the the association of CD151 with cell integrins and that CD151 endocytosis is for In the association of CD151 with such as by the CD151 endocytosis to be critical for the of CD151 tetraspanin X.A. Kim Liu J. Biol. 2003; PubMed Scopus Google Scholar) tetraspanin-enriched M.E. Cell Biol. 2003; PubMed Scopus Google Scholar). on the fact that CD151 physically associates with integrins, we integrins be this we used human dermal microvascular endothelial cells that CD151 and α3β1, α5β1, and α6β1 integrins. in α3β1, α5β1, and α6β1 integrins be in the intracellular vesicles of internalization. a of the α3β1, α5β1, and α6β1 integrins in intracellular vesicles that CD151 that CD151 with its associated integrins, and in the same compartments. In cells the vesicles for both CD151 and integrin vesicles with a in the of the intracellular vesicles for CD151 the integrin of M.D. Kim 2004; Scholar). The of CD151 in experiments the the internalization for CD151. is by the of the on the CD151 and/or of the association of and CD151. the of CD151 be in this vesicles that both CD151 and integrin found in cells and in the In intracellular vesicles, the integrin and CD151 with The vesicles that both CD151 and integrin found in of cells and In the of the integrin and CD151 whereas in of the cells integrin and CD151 internalization. and vesicles to an vesicular Liu and X. A. The of CD151 with integrins both and and the both consistent with The of of CD151 with the integrin with the and of the of CD151 with these integrins. the of CD151 and and found in of The endocytosis of the by as a the of in cells is markedly the of the CD151 and the integrins of CD151 with integrins during CD151 that with integrin the of of cells that the intracellular vesicles for both CD151 and integrin as the of cells in CD151 is as the for CD151. cells the CD151 in The and integrin The the of The of cells that the intracellular vesicles for both CD151 and integrin as the of cells in The CD151 is as the for CD151. cells the CD151 in The and integrin in a CD151 the of CD151 and its associated integrins be the same intracellular vesicular and CD151 is to associate with integrins, the in CD151 internalization by the in the endocytosis of its associated integrins. the of the CD151 the endocytosis of its associated integrins. we the internalization of integrins in CD151 and CD151 the integrin we the of internalization in the endocytosis and integrins, in of the cell integrin α6β1 CD151 and the indicating that the the of these integrins. is of cell integrin is associated with CD151 in and the for integrin be The attenuated endocytosis of CD151 in in the endocytosis of these integrins. the of and integrins in CD151 in the integrins with with whereas cellular CD151 in to the cellular distribution of CD151. The and integrins undergo endocytosis in the the of and trafficking of and integrins in diminished in the the cell surface, integrins completely in cells in the integrins on the cell in the of The and integrins in in CD151 and integrins in cell in the cells integrins likely to be integrins, this that the endocytosis and/or the trafficking endocytosis of and integrins CD151 endocytosis is in the of the found type and the the that the CD151 the internalization of integrins. that the endocytosis of integrins is we the of integrins CD151 and the the cell with a we the integrin on the of integrin to in the internalization of integrin in the with that in the The internalization of the integrin that physically associates with CD151 the of the integrin that physically associates with CD151 The of the integrins of the in the in the and the and in studies the integrin is the protein that is in the R.L. Kim F. Harler M.B. Reichner J. Hemler M.E. Mol. Biol. Cell. 1998; 9: 2751-2765Crossref PubMed Scopus (267) Google Scholar, R.L. Kim A.R. Hemler M.E. J. Biol. 2000; PubMed Scopus Google Scholar). cells with in the internalization we that integrin a that with human cytoplasmic that with cytoplasmic we that the integrins integrin by integrin and the of in cell to we the internalization of and integrins in type and and integrins the CD151 that cell to we found that the internalization of and integrins diminished in the especially and indicating that the the endocytosis of and integrins. with integrins, CD151 physically associates with such as and C. Kim E. Cell. Mol. Sci. PubMed Scopus Google Scholar, Kim van M.D. 2003; 24: PubMed Scopus Google Scholar). the in CD151 endocytosis the of we the endocytosis of and in we found that in endocytosis experiments in and In the in intracellular vesicles In these similar CD151 and the cells that endocytosis is by the CD151 The of in cells appears to be we protein a Kim M.E. J. Cell Biol. 1999; PubMed Scopus Google Scholar). the of the CD151 on endocytosis be in The YXXφ and of the YXXφ motif is a CD151 internalization. Mutation of the CD151 YXXφ motif in diminished internalization and trafficking of CD151 and in distribution of CD151 the cell and/or indicating that the YXXφ motif is a endocytosis trafficking for such as Kim G. J.A. D.J. G. J.P. Mol. Biol. Cell. 2002; 13: PubMed Scopus Google Scholar), A. and A. the YXXφ in the C-terminal cytoplasmic the YXXφ to cellular appears to be a common mechanism for the that this the that the YXXφ such as and endocytosis on on associated that this motif, such as and/or CD151. we found in this that its endocytosis markedly by the CD151 In this endocytosis be by its endocytosis that remains to be In of the mechanism that CD151 we that CD151 is a and and endocytosis Liu and X. A. Although the in endocytosis is in the CD151 the endocytosis is that the the of the cell CD151 that the during the cell in these of endocytosis The of cell likely the of its associated integrins with the of CD151 Also, the of CD151 is the the CD151 to CD151 and its internalization. the CD151 internalization by its endocytosis Tetraspanin and integrin to in the intracellular in an F. Kim E. J. Cell Biol. 1999; PubMed Scopus Google Scholar). integrin be in an that contains tetraspanin J. Kim R. J. 2002; PubMed Scopus Google Scholar). it is the same and the same for the that tetraspanin and integrin to the same vesicular this remains to be by in the The of CD151 and its associated integrins in vesicles that the same endocytosis to the same intracellular vesicular CD151 physically associates with it is likely that the same endocytosis internalization the of tetraspanin with integrin be an of the well CD151 Cell regulates cell the mechanism remains in this the YXXφ motif the CD151-promoted cell migration on and completely in cell migration with the in the internalization of the CD151 that CD151 endocytosis and/or trafficking is for cell is the to that the trafficking of tetraspanin a role in regulating cell of such as found to cell migration Kim Y. H. M. J. Cell Biol. PubMed Scopus Google Scholar). it appears that endocytosis in the role for vesicular trafficking in regulating cell migration PubMed Scopus Google Scholar). On the endocytosis is by a in cell migration Kim Development (Camb.). 2002; PubMed Google Scholar). On the the of cells and cells Kim A. M. J. Cell Biol. PubMed Scopus Google Scholar). cell is a common feature of and such as and CD151 present in intracellular vesicles Kim van M.D. 2003; 24: PubMed Scopus Google Scholar, Kim S. J. 1997; PubMed Scopus Google Scholar). trafficking be a common that on for regulating cell motility. CD151 internalization cell that the association of CD151 with tetraspanin C. Kim E. Cell. Mol. Sci. PubMed Scopus Google Scholar) S. Sci. S. A. 2002; PubMed Scopus Google Scholar) M.E. Cell Biol. 2003; PubMed Scopus Google Scholar), which by cell and the CD151 internalization endocytosis of its associated tetraspanin TEM, and the in the and of we in this that trafficking of a by CD151 CD151 regulates the trafficking of it is the of CD151 trafficking in the of with and the of vesicles to be in The of CD151 in the is for cells to integrin during cell migration is important as its in Kim Cell. 1996; PubMed Scopus Google Scholar). The integrins in the of cells be the cell the plasma membrane and/or and to the cell Kim M.A. K. G. A.R. 2003; PubMed Scopus Google Scholar). The of integrin endocytosis and of vesicles the cell in J. PubMed Scopus Google Scholar, C. Kim A. J. Cell Biol. PubMed Scopus Google Scholar) to the that integrins plasma membrane the of cells and likely to plasma membrane the to with Cell. 1996; PubMed Scopus Google Scholar). The trafficking of integrins is to cell migration Kim C. Cell Biol. 1998; PubMed Scopus Google Scholar). integrin distribution is in cells and by the of endocytosis the and to the M.A. Kim PubMed Scopus Google Scholar). during cell integrin and vesicles the of a cell the to the of the Kim D.J. K. J. Cell Biol. PubMed Scopus Google Scholar, L.M. Kim M.A. Blood. 2000; PubMed Google Scholar, Kim 2006; PubMed Scopus Google Scholar). The in integrin for its trafficking in cell migration in the YXXφ motif in the integrin is for of the integrins, and a of this motif integrin cell migration M. Kim G. E. J.R. R. J. 1999; PubMed Scopus Google Scholar, M. Kim S. M.C. E. R. J.R. C. R. Mol. Biol. Cell. PubMed Scopus Google Scholar). The trafficking of integrin Kim A. K. K. J.A. J. J. Cell Biol. 2006; PubMed Scopus Google Scholar, J. Kim R. J. 2002; PubMed Scopus Google Scholar, M. Kim S. M.C. E. R. J.R. C. R. Mol. Biol. Cell. PubMed Scopus Google Scholar, Kim A. S. M.J. J. 1999; PubMed Scopus Google Scholar, M. Kim S. A. van J. Biol. PubMed Scopus Google Scholar, Kim Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar, Kim V. J. J. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar, Kim J. 2004; PubMed Scopus Google Scholar, J. Kim J. Cell. 9: PubMed Scopus Google Scholar). the internalization of integrin in cancer cells and the the cell on Kim A. S. M.J. J. 1999; PubMed Scopus Google Scholar). Regulation of cell migration CD151 trafficking a integrin trafficking is in this regulatory The association of CD151 with LN-binding integrins such as α3β1, α6β1, α6β4, and α7β1 that CD151 regulates the trafficking of these integrins. Although CD151 to integrin M.E. Cell Biol. 2003; PubMed Scopus Google Scholar), this integrin be of a tetraspanin and associates with CD151 (1Sincock P.M. Kim S. Parton R.G. Berndt M.C. Gamble J.R. Ashman L.K. J. Cell Sci. 1999; 112: 833-844Crossref PubMed Google Scholar, H. Kim K. K. S. J. 1998; Google Scholar). the trafficking of integrin be by CD151 CD151 is expressed in cells such as in which is of the integrins. the endocytosis the trafficking the of integrins such as α3β1, α6β1, and is markedly attenuated by the CD151 the endocytosis of integrin CD151 with the diminished cell migration (8Winterwood N.E. Kim A. Meland M.N. Ashman L.K. Stipp C.S. Mol. Biol. Cell. 2006; 17: 2707-2721Crossref PubMed Scopus (113) Google Scholar). Although studies that integrin endocytosis (8Winterwood N.E. Kim A. Meland M.N. Ashman L.K. Stipp C.S. Mol. Biol. Cell. 2006; 17: 2707-2721Crossref PubMed Scopus (113) Google Scholar, Kim S. L.K. X.A. J. Biol. PubMed Scopus Google Scholar), is the to the in tetraspanin that the trafficking of its associated integrins and to a mechanism for CD151 regulates integrin The fact that CD151 the trafficking of its associated integrins, which the integrins in the R. Kim N. S. Y. Y. M. J. Hasegawa H. Sekiguchi K. Sci. S. A. PubMed Scopus Google Scholar) the integrins in cell migration that CD151 integrin to integrin trafficking in on these we that integrins in cell migration the association of CD151 with integrin α3β1, the of CD151 with integrins M.E. Cell Biol. 2003; PubMed Scopus Google Scholar). in a of integrins is by in of human integrin it is that the trafficking of and α6β1 integrins by human CD151 in Although we the of the CD151 on the internalization of integrin in we that the integrin trafficking be attenuated of the association of CD151 with integrin α3β1, which is and α6β1 integrins. the cytoplasmic of many integrin endocytosis the trafficking of integrins be by with tetraspanin TEM, the trafficking and/or of integrins be modified by the trafficking of associated such as the YRSL motif of CD151. the trafficking of integrins and by trafficking whereas tetraspanin of and a to the trafficking of its associated such as remains to be in a CD151 the trafficking of integrins in Given the fact that CD151 is in and J.E. Kim P.C. Liu J.-M. Quiqley J.P. Cancer Res. 1999; 59: 3812-3820PubMed Google Scholar), this to a and mechanism that the trafficking of integrins in cancer of the of cell movement and the and of Also, the fact that in mice Y. Kim A.R. Butterfield C.E. Hopkins B.D. Benjamin L.E. Kaipainen A. Hemler M.E. Blood. 2007; 109: 1524-1532Crossref PubMed Scopus (135) Google Scholar), the role of CD151 in regulating the trafficking of integrins in endothelial cell for and is an to be and for critical of the used in this