Tumor cell autocrine motility factor receptor

  • Ivan R. Nabi
  • Hideomi Watanabe
  • Steve Silletti
  • Avraham Raz
Part of the Experientia Supplementum book series (EXS, volume 59)


The ability to locomote and migrate is fundamental to the acquisition of invasive and metastatic properties by tumor cells. Autocrine motility factor (AMF) is a cytokine produced by various tumor cells which stimulates their in vitro motility and in vivo lung-colonizing ability. AMF stimulates cell motility via a receptor-mediated signalling pathway. Signal transduction following binding of AMF to its receptor, a cell surface glycoprotein of 78 kD (gp78), is mediated by a pertussis toxin sensitive G protein, inositol phosphate production and the phosphorylation of gp78. AMF induces gp78 internalization to intracellular tubulovesicles and transport to the leading edge stimulating pseudopodial protrusion and cell motility.


Pertussis Toxin Motile Cell Inositol Triphosphate Motility Factor Cell Locomotion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Abercrombie, M., Heaysman, J. E. M., and Pegrum, S. M. (1970) The locomotion of fibroblasts in culture III. Movement of particles on the dorsal surface of the leading lamella. Exp. Cell Res. 62: 389–398.CrossRefGoogle Scholar
  2. Albrecht-Buehler, G. (1977) The phagokinetic tracks of 3T3 cells. Cell 11: 395–404.CrossRefGoogle Scholar
  3. Atnip, K. D., Carter, L. M., Nicolson, G. L., and Dabbous, M. K. (1987) Chemotactic response of rat mammary adenocarcinoma cell clones to tumor-derived cytokines. Biochem. Biophys. Res. Comm. 146: 996–1002.CrossRefGoogle Scholar
  4. Bareis, D. L., Hirata, F., Schiffmann, E., and Axelrod, J. (1982) Phospholipid metaboHsm, calcium flux, and the receptor mediated induction of Chemotaxis in rabbit neutrophils. J. Cell Biol. 93: 690–697.CrossRefGoogle Scholar
  5. Bergmann, J. E., Kupfer, A., and Singer, S. J. (1983) Membrane insertion at the leading edge of motile fibroblasts. Proc. Natl. Acad. Sci. USA 80: 1367–1371.CrossRefGoogle Scholar
  6. Bomsel, M., Parton, R., Kuznetsov, S. A., Schroer, T. A., and Gruenberg J. (1990) Microtubule- and motor-dependent fusion in vitro between apical and basolateral endocytic vesicles from MDCK cells. Cell 62: 719–731.CrossRefGoogle Scholar
  7. Brandt, S. J., Dougherty, R. W., Lapetina, E. G., and Niedel J. E. (1985) Pertussis toxin inhibits chemotactic peptide-stimulated generation of inositol phosphates and lysosomal enzyme secretion in human leukemic (HL-60) cells. Proc. Natl. Acad. Sci. USA 82: 3277–3280.CrossRefGoogle Scholar
  8. Bretscher, M. S. (1983) Distribution of receptors for transferrin and low density Upoprotein on the surface of giant HeLa cells. Proc. Natl. Acad. Sci. USA 80: 454–458.CrossRefGoogle Scholar
  9. Bretscher, M. S. (1984) Endocytosis: relation to capping and cell locomotion. Science 226: 681–686.CrossRefGoogle Scholar
  10. Bretscher, M. S. (1989) Endocytosis and recycHng of the fibronectin receptor in CHO cells. EMBO J. 8: 1341–1348.Google Scholar
  11. Bretscher, M. S. (1988) Fibroblasts on the move. J. Cell Biol. 106: 235–237.CrossRefGoogle Scholar
  12. Cooper, M. S., Cornell-Bell, A. H., Chemjavsky, A., Dani, J. W., and Smith, S. J. (1990). Tubulovesicular processes emerge from trans-Golgi cistemaer extend along microtubules, and interiink adjacent trans-Golgi elements into a reticulum. Cell 61: 135–145.CrossRefGoogle Scholar
  13. Croze, E., Ivanov, I. E., Kreibich, G., Adesnik, M., Sabatini, D. D., and Rosenfeld, M. G. (1989) Endolyn-78, a membrane glycoprotein present in morphologically diverse components of the endosomal and lysosomal compartments: implication for lysosome biogenesis. J. Cell Biol. 108: 1597–1613.CrossRefGoogle Scholar
  14. De Biasio, R. L., Wang, L.-L., Fisher, G. W., and Taylor, D. L. (1988) The dynamic distribution of fluorescent analogues of actin and myosin at the leading edge of migrating Swiss 3T3 fibroblasts. J. Cell Biol. 107: 2631–2645.CrossRefGoogle Scholar
  15. de Brabander, M., Nuydens, R., Geerts, H., and Hopkins, C. R. (1988). Dynamic behavior of the transferrin receptor followed in living epidermoid carcinoma (A431) cells with Nanovid microscopy. Cell Motil. Cytoskel. 9: 30–47.CrossRefGoogle Scholar
  16. Eberle, M., Traynor-Kaplan, A. E., Sklar, L. A., and Norgauer, J. (1990) Is there a relationship between phosphatidylinositol triphosphate and F-actin polymerization in human neutrophils. J. Biol. Chem. 265: 16725–16728.Google Scholar
  17. Eckstein, D. J., and Shur, B. D. (1989) Laminin induces the stable expression of surface galactosyltransferase on lamellipodia of migrating cells. J. Cell Biol 108: 2507–2517.CrossRefGoogle Scholar
  18. Gruenberg, J., Griffiths, G., and Howell, K. E. (1989) Characterization of the early endosome and putative endocytic carrier vesicles in vivo and with an assay of vesicle fusion in vitro. J. Cell Boil. 108: 1301–1316.CrossRefGoogle Scholar
  19. Guirgius, R., Margulies, I., Tarboletti, G., Schiffmann, E., and Liotta, L. (1987) Cytokine-in-duced pseudopodial protrusion is coupled to tumor cell migration. Nature 329: 261–263.CrossRefGoogle Scholar
  20. Heffernan, M., Yousefi, S., and Dennis, J. W. (1989) Molecular characterization of P2B/ LAMP-1, a major protein target of a metastasis-associated oligosaccharide structure. Cancer Res. 49: 6077–6084.Google Scholar
  21. Hendrix, M. J. C., Wood, W. R., Seftor, E. A., Lotan, D., Nakiyama, M., Misiorowski, R. L., Seftor, R. E. B., Stotler-Stevenson, W. G., Bevacqua, S. J., Liotta, L., Sobel, M. E., Raz, A., and Lotan, R. (1990) Retinoic acid inhibition of human melanoma cell invasion through a reconstituted basement membrane and its relation to decreases in the expression of proteolytic enzymes and motility factor receptor. Cancer Res. 50: 4121–4130.Google Scholar
  22. Heuser, J. (1989) Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH. J. Cell Biol. 108: 855–864.CrossRefGoogle Scholar
  23. Hopkins, C. R., Gibson, A., Shipman, M., and Miller, K. (1990) Movement of internalized ligand receptor complexes along a continuous endosomal reticulum. Nature 346: 335–339.CrossRefGoogle Scholar
  24. Hunziker, W., Male, P., and Mellman, L (1990) Differential microtubule requirements for transcytosis in MDCK cells. EMBO J. 9: 3515–3525.Google Scholar
  25. Ishihara, A., Holifield, B., and Jacobson, K. (1988) Analysis of lateral redistribution of a monoclonal antibody complex plasma membrane glycoprotein which occurs during cell locomotion. J. Cell Biol. 106: 329–343.CrossRefGoogle Scholar
  26. Johns, J. A., Brock, A.M., and Pardee, J. D. (1988) Colocalization of F-actin and 34-kilodalton actin bundling protein in Dictostelium amoebae and cultured fibroblasts. Cell Motil. Cytoskel. 9: 205–218.CrossRefGoogle Scholar
  27. Kelly, R. B. (1990) Microtubules, membrane traffic and cell organization. Cell 61: 5–7.CrossRefGoogle Scholar
  28. Kohn, E. C., Liotta, L. A., and Schiffmann, E. (1990) Autocrine motility factor stimulates a three-fold increase in inositol phosphate in human melanoma cells. Biochem. Biophys. Res. Comm. 166: 757–764.CrossRefGoogle Scholar
  29. Kornfeld, S., and Mellman, L (1989) The biogenesis of lysosomes. Ann. Rev. Cell Biol. 5: 483–525.CrossRefGoogle Scholar
  30. Kucik, D. F., Elson, E. L., and Sheetz, M. P. (1990) Cell migration does not produce membrane flow. J. Cell Biol. 111: 1617–1622.CrossRefGoogle Scholar
  31. Kupfer, A., Louvard, D., and Singer, S. J. (1982). 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 79: 2603–2607.CrossRefGoogle Scholar
  32. Lam, W. C., Delikatny, J., Orr, F. W., Wass, J., Varani, J., and Wand, P. A. (1981) The chemotactic response of tumor cells. A model for cancer metastasis. Am. J. Pathol. 104: 69–76.Google Scholar
  33. Liotta, L. A., Mandler, R., Murano, G., Katz, D. A., Gordon, R. K., Chiang, P. K., and Schiff’mann, E. (1986) Tumor cell autocrine motility factor. Proc. Natl. Acad. Sci. USA 83: 3302–3306.CrossRefGoogle Scholar
  34. Lippincott-Schwartz, J., and Fambrough, D. M. (1986) Lysosomal membrane dynamics: structure and interorganelle movement of a major lysosomal membrane glycoprotein. J. Cell Biol. 102: 1593–1605.CrossRefGoogle Scholar
  35. Lippincott-Schwartz, J., and Fambrough, D. M. (1987) Cycling of the integral membrane glycoprotein, LEP 100, between plasma membrane and lysosomes: kinetic and morphological analysis. Cell 49: 669–677.CrossRefGoogle Scholar
  36. Lippincott-Schwartz, J., Donaldson, J. G., Schweizer, A., Berger, E. G., Hauri, H.-P., Yuan, L. C., and Klausner, R. D. (1990) Microtubule-dependent retrograde transport of proteins into the ER in the presence of Brefeldin A suggests an ER recycling pathway. Cell 60: 821–836.CrossRefGoogle Scholar
  37. Matter, K., Bücher, K., and Hauri, H.-P. (1990) Microtubule perturbation retards both the direct and the indirect apical pathway but does not affect sorting of plasma membrane proteins in intestinal epithelial cells (Caco-2). EMBO J. 9: 3163–3170.Google Scholar
  38. McCarthy, J. B., Basara, M. L., Palm, S. L., Sas, F., and Furcht, T. L. (1985) The role of cell adhesion proteins laminin and fibronectin in the movement of malignant and metastatic cells. Cancer Met. Rev. 4: 125–152.CrossRefGoogle Scholar
  39. Mithieux, G., and Rousset, B. (1989) Identification of a lysosomal membrane protein which could mediate ATP-dependent stable association of lysosomes to microtubules. J. Biol. Chem. 264: 4664–4668.Google Scholar
  40. Nabeshima, K., Kataska, H., and Koona, M. (1986) Enhanced migration of tumor cells in response to collagen degradation products and tumor cell collagenelytic activity. Invas. Metas. 6: 270–286.Google Scholar
  41. Nabi, I. R., and Raz, A. (1987) Cell shape modulation alters glycosylation of a metastatic melanoma cell surface antigen. Int. J. Cancer 40: 396–401.CrossRefGoogle Scholar
  42. Nabi, I. R., and Raz, A. (1988) Loss of metastatic responsiveness to cell shape modulation in a newly characterized B16 melanoma adhesive variant. Cancer Res. 48: 1258–1264.Google Scholar
  43. Nabi, I. R., Watanabe, H., and Raz, A. (1990) Identification of B16-F1 melanoma autocrine motility-Hke factor receptor. Cancer Res. 50: 409–414.Google Scholar
  44. Nabi, I. R., Watanabe, H., and Raz, A. (1990a). Intracellular localization of a motility factor receptor to tubulovesicles. Submitted.Google Scholar
  45. Nicolson, G. L. (1988) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Met. Rev. 7: 143–188.CrossRefGoogle Scholar
  46. Raz, A., and Ben-Ze’ev, A. (1983) Modulation of the metastatic capability in B16 melanoma by cell shape. Science 221: 1307–1310.CrossRefGoogle Scholar
  47. Raz, A., and Ben-Ze’ev, A. (1987) Cell-contact and architecture of mahgnant cells and their relationship to metastasis. Cancer Met. Rev. 6: 3–21.CrossRefGoogle Scholar
  48. Rindler, M. J., Ivanov, I. E., and Sabatini, D. D. (1987) Microtubule-acting drugs lead to a non-polarized delivery of the influence hemagglutinin to the cell surface of polarized Madin-Darby canine kidney cells. J. Cell Biol. 104: 231–241.CrossRefGoogle Scholar
  49. Rogalski, A. A., Bergmann, J. E., and Singer, S. J. (1984) Effect of microtubule assembly status on the intracellular processing and surface expression of an integral protein of the plasma membrane. J. Cell Biol. 99: 1101–1109.CrossRefGoogle Scholar
  50. Rosen, E. M., Meromsky, L., Setter, E., Vinter, D. W., and Goldberg, I. D. (1990) Quantitation of cytokine-stimulated migration of endothelium and epithelium by a new assay using microcarrier beads. Exp. Cell Res. 186: 22–31.CrossRefGoogle Scholar
  51. Ryan, G. B., Borysenko, J. Z., and Karnovsky, M. J. (1974) Factors affecting the redistribution of surface-bound concanavalin A on human polymorphonuclear leukoctyes. J. Cell Biol. 62: 351–365.CrossRefGoogle Scholar
  52. Schliwa, M., Euteneuer, U., Bulinski, J. C., and Izant, J. G. (1981) Calcium lability of cytoplasmic microtubules and its modulation by microtubule-associated proteins. Proc. Natl. Acad. Sci. U.S.A. 78: 1037–1041.CrossRefGoogle Scholar
  53. Schor, S. L., Schor, A. M., Grey, A. M., and Rushton, G. (1988) Foetal and cancer patient fibroblasts produce an autocrine migration stimulating factor not made by normal adult cells. J. Cell Sci. 90: 391–399.Google Scholar
  54. Schreiner, G. F., Braun, J., and Unanue, E. R. (1976) Spontaneous redistribution of surface immunoglobulin in the motile B lymphocyte. J. Exp. Med. 144: 1683–1688.CrossRefGoogle Scholar
  55. Shefcyk, J., Yassin, R., Volpi, M., and Molski, T. F. P., Naccache, P. H., Munoz, J. J., Becker, E. L., Feinstein, M. B., and Sha’afi, R. I. (1985). Pertussis toxin but not cholera toxin inhibits the stimulated increase in actin association with the cytoskeleton in rabbit neutrophils: role of the “G proteins” in stimulation-response coupling. Biochem. Biophys. Res. Comm. 126: 174–181.CrossRefGoogle Scholar
  56. Silletti, S., Watanabe, H., Hogan, V., Nabi, I. R., and Raz, A. (1991) Purification of B16-F1 melanoma autocrine motility factor and its receptor. Submitted.Google Scholar
  57. Singer, S. J., and Kupfer, A. (1986) The directed migration of eukaryotic cells. Ann. Rev. Cell Biol. 2: 337–365.CrossRefGoogle Scholar
  58. Small, J. W., Isenberg, G., and Celis, J. E. (1978) The polarity of actin at the leading edge of cultured cells. Nature 272: 638–639.CrossRefGoogle Scholar
  59. Smith, C. D., Cox, C. C., and Snyderman, R. (1986) Receptor coupled activation of phosphoinositide-specific phosphohpase C by an N protein. Science 232: 97–100.CrossRefGoogle Scholar
  60. Stoker, M., Gherardi, E., Perryman, M., and Grey, J. (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327: 239–242.CrossRefGoogle Scholar
  61. Stracke, M. L., Guirguis, R., Liotta, L. A., and Schiffmann, E. (1987) Pertussis toxin inhibits stimulated motility independently of the adenylate cyclase pathway in human melanoma cells. Biochem. Biophys. Res. Comm. 164: 339–345.CrossRefGoogle Scholar
  62. Swanson, J., Bushneil, A., and Silverstein, S. C. (1987). Tubular lysosome morphology and distribution within macrophages depend on the integrity of cytoplasmic microtubules. Proc. Natl. Acad. Sci. USA 84: 1921–1925.CrossRefGoogle Scholar
  63. Ullrich, A., and Schlessinger, J. (1990) Signal tranduction by receptors with tyrosine kinase activity. Cell 61: 203–212.CrossRefGoogle Scholar
  64. Verghese, M. W., Smith, C. D., and Snyderman, R. (1985) Potential role for a guanine nucleotide regulatory protein in chemoattractant receptor mediated polyphosphoinositide metabolism, mobilization and cellular responses in leukocytes. Biochem. Biophys. Res. Comm. 127: 450–457.CrossRefGoogle Scholar
  65. Volk, T., Geiger, B., and Raz, A. (1984) Motility of high and low metastatic neoplastic cells. Cancer Res. 44: 811–824.Google Scholar
  66. Watanabe, H., Nabi, I. R., and Raz, A. (1991a) The relationship between motility factor receptor internalization and the lung colonization capacity of murine melanoma cells. Cancer Res. in press.Google Scholar
  67. Watanabe, H., Carmi, P., Hogan, V., Raz, T., Silletti, S., Nabi, I. R., and Raz, A. (1991b) Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J. Biol. Chem. in press.Google Scholar
  68. Yoshida, K., Ozaki, T., Ushijina, K., and Hayashi, H. (1970) Studies on the mechanisms of invasion in cancer. I. Isolation and purification of a factor chemotactic for cancer cells. int. J. Cancer 6: 123–132.CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 1991

Authors and Affiliations

  • Ivan R. Nabi
    • 1
  • Hideomi Watanabe
    • 1
  • Steve Silletti
    • 1
  • Avraham Raz
    • 1
  1. 1.Cancer Metastasis ProgramMichigan Cancer FoundationDetroitUSA

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