Processing of MIA protein during melanoma cell migration
Jennifer Schmidt
Institute of Pathology, Molecular Pathology, University of Regensburg, Regensburg, Germany
Search for more papers by this authorCorresponding Author
Anja-Katrin Bosserhoff
Institute of Pathology, Molecular Pathology, University of Regensburg, Regensburg, Germany
Fax: +49-941-944-6602.
Institute of Pathology, Molecular Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, GermanySearch for more papers by this authorJennifer Schmidt
Institute of Pathology, Molecular Pathology, University of Regensburg, Regensburg, Germany
Search for more papers by this authorCorresponding Author
Anja-Katrin Bosserhoff
Institute of Pathology, Molecular Pathology, University of Regensburg, Regensburg, Germany
Fax: +49-941-944-6602.
Institute of Pathology, Molecular Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, GermanySearch for more papers by this authorAbstract
MIA (melanoma inhibitory activity) protein, identified as a small 11 kDa protein highly expressed and secreted by malignant melanoma cells, plays an important functional role in melanoma development, progression and tumor cell invasion. Recent data describe a direct interaction of MIA protein with cell adhesion receptors integrin α4β1 and integrin α5β1 and extracellular matrix molecules. By modulating integrin activity MIA protein mediates detachment of melanoma cells from surrounding structures resulting in enhanced invasive and migratory potential. However, until today a detailed understanding of the processes of MIA function is missing. In this study, we show that after binding of MIA protein to integrin α5β1, MIA protein is internalized together with this cell adhesion receptor at the cell rear. This mechanism enables tumor cells to migrate in a defined direction as appropriate for invasion processes. Treatment of melanoma cells with PKC-inhibitors strongly reduced internalization of MIA protein. Endocytosis is followed by dissociation of MIA–integrin complexes. In acidic vesicles MIA protein is degraded while integrins are recycled. Treatment of melanoma cells with MIA inhibitory peptides almost completely blocked the MIA protein uptake into cells. As MIA protein has a major contribution to the aggressive characteristics of malignant melanoma in particular to formation of metastasis, it is important to elucidate the MIA functional mechanism in tumor cells to find novel therapeutic strategies in the fight against skin cancer. © 2009 UICC
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| IJC_24508_sm_SupFig1.tif747.3 KB | Supporting Figure 1. |
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| IJC_24508_sm_SupFig3.tif4.8 MB | Supporting Figure 3. |
| IJC_24508_sm_SupFig4.tif3 MB | Supporting Figure 4. |
| IJC_24508_sm_SupFig5.tif3.1 MB | Supporting Figure 5. |
| IJC_24508_sm_SupFig6.tif2.4 MB | Supporting Figure 6. |
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References
- 1 Bosserhoff AK,Kaufmann M,Kaluza B,Bartke I,Zirngibl H,Hein R,Stolz W,Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res 1997; 57: 3149–53.
- 2 Bosserhoff AK,Stoll R,Sleeman JP,Bataille F,Buettner R,Holak TA. Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity. Lab Invest 2003; 83: 1583–94.
- 3 Guba M,Bosserhoff AK,Steinbauer M,Abels C,Anthuber M,Buettner R,Jauch KW. Overexpression of melanoma inhibitory activity (MIA) enhances extravasation and metastasis of A-mel 3 melanoma cells in vivo. Br J Cancer 2000; 83: 1216–22.
- 4 Bosserhoff AK,Echtenacher B,Hein R,Buettner R. Functional role of melanoma inhibitory activity in regulating invasion and metastasis of malignant melanoma cells in vivo. Melanoma Res 2001; 11: 417–21.
- 5 Dreau D,Bosserhoff AK,White RL,Buettner R,Holder WD. Melanoma-inhibitory activity protein concentrations in blood of melanoma patients treated with immunotherapy. Oncol Res 1999; 11: 55–61.
- 6 Stahlecker J,Gauger A,Bosserhoff A,Buttner R,Ring J,Hein R. MIA as a reliable tumor marker in the serum of patients with malignant melanoma. Anticancer Res 2000; 20: 5041–4.
- 7 Stoll R,Renner C,Ambrosius D,Golob M,Voelter W,Buettner R,Bosserhoff AK,Holak TA. Sequence-specific 1H, 13C, and 15N assignment of the human melanoma inhibitory activity (MIA) protein. J Biomol NMR 2000; 17: 87–8.
- 8 Stoll R,Renner C,Zweckstetter M,Bruggert M,Ambrosius D,Palme S,Engh RA,Golob M,Breibach I,Buettner R,Voelter W,Holak TA et al. The extracellular human melanoma inhibitory activity (MIA) protein adopts an SH3 domain-like fold. EMBO J 2001; 20: 340–9.
- 9 Stoll R,Renner C,Buettner R,Voelter W,Bosserhoff AK,Holak TA. Backbone dynamics of the human MIA protein studied by (15)N NMR relaxation: implications for extended interactions of SH3 domains. Protein Sci 2003; 12: 510–19.
- 10 Lougheed JC,Holton JM,Alber T,Bazan JF,Handel TM. Structure of melanoma inhibitory activity protein, a member of a recently identified family of secreted proteins. Proc Natl Acad Sci USA 2001; 98: 5515–20.
- 11 Stoll R,Bosserhoff A. Extracellular SH3 domain containing proteins—features of a new protein family. Curr Protein Pept Sci 2008; 9: 221–6.
- 12 Bauer R,Humphries M,Fassler R,Winklmeier A,Craig SE,Bosserhoff AK. Regulation of integrin activity by MIA. J Biol Chem 2006; 281: 11669–77.
- 13 Bretscher MS. Circulating integrins: alpha 5 beta 1, alpha 6 beta 4 and Mac-1, but not alpha 3 beta 1, alpha 4 beta 1 or LFA-1. EMBO J 1992; 11: 405–10.
- 14 Caswell PT,Norman JC. Integrin trafficking and the control of cell migration. Traffic 2006; 7: 14–21.
- 15 Arndt S,Poser I,Moser M,Bosserhoff AK. Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Mol Cell Neurosci 2007; 34: 603–11.
- 16 Kupfer A,Louvard D,Singer SJ. Polarization of the Golgi apparatus and the microtubule-organizing center in cultured fibroblasts at the edge of an experimental wound. Proc Natl Acad Sci USA 1982; 79: 2603–7.
- 17 Magdalena J,Millard TH,Machesky LM. Microtubule involvement in NIH 3T3 Golgi and MTOC polarity establishment. J Cell Sci 2003; 116: 743–56.
- 18 Prigozhina NL,Waterman-Storer CM. Protein kinase D-mediated anterograde membrane trafficking is required for fibroblast motility. Curr Biol 2004; 14: 88–98.
- 19 Altankov G,Grinnell F. Fibronectin receptor internalization and AP-2 complex reorganization in potassium-depleted fibroblasts. Exp Cell Res 1995; 216: 299–309.
- 20 Liu L,He B,Liu WM,Zhou D,Cox JV,Zhang XA. Tetraspanin CD151 promotes cell migration by regulating integrin trafficking. J Biol Chem 2007; 282: 31631–42.
- 21 Nishimura T,Kaibuchi K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell 2007; 13: 15–28.
- 22 Jones MC,Caswell PT,Norman JC. Endocytic recycling pathways: emerging regulators of cell migration. Curr Opin Cell Biol 2006; 18: 549–57.
- 23 Pellinen T,Ivaska J. Integrin traffic. J Cell Sci 2006; 119: 3723–31.
- 24 Ramsay AG,Marshall JF,Hart IR. Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev 2007; 26: 567–78.
- 25 Tomasini BR,Mosher DF. Vitronectin. Prog Hemostat Thromb 1991; 10: 269–305.
- 26 Panetti TS,Wilcox SA,Horzempa C,McKeown-Longo PJ. Alpha v beta 5 integrin receptor-mediated endocytosis of vitronectin is protein kinase C-dependent. J Biol Chem 1995; 270: 18593–7.
- 27 Pijuan-Thompson V,Gladson CL. Ligation of integrin alpha5beta1 is required for internalization of vitronectin by integrin alphavbeta3. J Biol Chem 1997; 272: 2736–43.
- 28 Godyna S,Liau G,Popa I,Stefansson S,Argraves WS. Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1. J Cell Biol 1995; 129: 1403–10.
- 29 Memmo LM,McKeown-Longo P. The alphavbeta5 integrin functions as an endocytic receptor for vitronectin. J Cell Sci 1998; 111: 425–33.
- 30 Murphy-Ullrich JE,Mosher DF. Interactions of thrombospondin with endothelial cells: receptor-mediated binding and degradation. J Cell Biol 1987; 105: 1603–11.
- 31 Wienke D,MacFadyen JR,Isacke CM. Identification and characterization of the endocytic transmembrane glycoprotein Endo180 as a novel collagen receptor. Mol Biol Cell 2003; 14: 3592–604.
- 32 Sottile J,Chandler J. Fibronectin matrix turnover occurs through a caveolin-1-dependent process. Mol Biol Cell 2005; 16: 757–68.
- 33 Shi F,Sottile J. Caveolin-1-dependent {beta}1 integrin endocytosis is a critical regulator of fibronectin turnover. J Cell Sci 2008; 121: 2360–71.
- 34 Bates RC,Lincz LF,Burns GF. Involvement of integrins in cell survival. Cancer Metastasis Rev 1995; 14: 191–203.
- 35 Boudreau N,Sympson CJ,Werb Z,Bissell MJ. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 1995; 267: 891–3.
- 36 Clarke AS,Lotz MM,Chao C,Mercurio AM. Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain. J Biol Chem 1995; 270: 22673–6.
- 37 Langholz O,Rockel D,Mauch C,Kozlowska E,Bank I,Krieg T,Eckes B. Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by alpha 1 beta 1 and alpha 2 beta 1 integrins. J Cell Biol 1995; 131: 1903–15.
- 38 Varner JA,Emerson DA,Juliano RL. Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol Biol Cell 1995; 6: 725–40.
- 39 Scott G,Ryan DH,McCarthy JB. Molecular mechanisms of human melanocyte attachment to fibronectin. J Invest Dermatol 1992; 99: 787–94.
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