Skip to main content
NCBI home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1996 Jul 1;134(1):165–179. doi: 10.1083/jcb.134.1.165

The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration

PMCID: PMC2120913  PMID: 8698812

Abstract

Mutations in the adenomatous polyposis coli (APC) gene are linked to polyp formation in familial and sporadic colon cancer, but the functions of the protein are not known. We show that APC protein localizes mainly to clusters of puncta near the ends of microtubules that extend into actively migrating regions of epithelial cell membranes. This subcellular distribution of APC protein requires microtubules, but not actin filaments. APC protein-containing membranes are actively involved in cell migration in response to wounding epithelial monolayers, addition of the motorgen hepatocyte growth factor, and during the formation of cell-cell contacts. In the intestine, APC protein levels increase at the crypt/villus boundary, where cell migration is crucial for enterocyte exit from the crypt and where cells accumulate during polyp formation that is linked to mutations in the microtubule-binding domain of APC protein. Together, these data indicate that APC protein has a role in directed cell migration.

Full Text

The Full Text of this article is available as a PDF (10.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Behrens J., Vakaet L., Friis R., Winterhager E., Van Roy F., Mareel M. M., Birchmeier W. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol. 1993 Feb;120(3):757–766. doi: 10.1083/jcb.120.3.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bishop D. T., Hall N. R. The genetics of colorectal cancer. Eur J Cancer. 1994;30A(13):1946–1956. doi: 10.1016/0959-8049(94)00385-i. [DOI] [PubMed] [Google Scholar]
  3. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  4. Cooper M. W., Smith S. J. A real-time analysis of growth cone-target cell interactions during the formation of stable contacts between hippocampal neurons in culture. J Neurobiol. 1992 Sep;23(7):814–828. doi: 10.1002/neu.480230704. [DOI] [PubMed] [Google Scholar]
  5. Funayama N., Fagotto F., McCrea P., Gumbiner B. M. Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. J Cell Biol. 1995 Mar;128(5):959–968. doi: 10.1083/jcb.128.5.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. doi: 10.1016/0092-8674(81)90021-0. [DOI] [PubMed] [Google Scholar]
  7. Gumbiner B. M. Signal transduction of beta-catenin. Curr Opin Cell Biol. 1995 Oct;7(5):634–640. doi: 10.1016/0955-0674(95)80104-9. [DOI] [PubMed] [Google Scholar]
  8. Hamilton S. R., Liu B., Parsons R. E., Papadopoulos N., Jen J., Powell S. M., Krush A. J., Berk T., Cohen Z., Tetu B. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839–847. doi: 10.1056/NEJM199503303321302. [DOI] [PubMed] [Google Scholar]
  9. Hermiston M. L., Gordon J. I. In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J Cell Biol. 1995 Apr;129(2):489–506. doi: 10.1083/jcb.129.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hermiston M. L., Gordon J. I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science. 1995 Nov 17;270(5239):1203–1207. doi: 10.1126/science.270.5239.1203. [DOI] [PubMed] [Google Scholar]
  11. Hinck L., Nelson W. J., Papkoff J. Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin. J Cell Biol. 1994 Mar;124(5):729–741. doi: 10.1083/jcb.124.5.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hinck L., Näthke I. S., Papkoff J., Nelson W. J. Beta-catenin: a common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. Trends Biochem Sci. 1994 Dec;19(12):538–542. doi: 10.1016/0968-0004(94)90057-4. [DOI] [PubMed] [Google Scholar]
  13. Hinck L., Näthke I. S., Papkoff J., Nelson W. J. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol. 1994 Jun;125(6):1327–1340. doi: 10.1083/jcb.125.6.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hülsken J., Birchmeier W., Behrens J. E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J Cell Biol. 1994 Dec;127(6 Pt 2):2061–2069. doi: 10.1083/jcb.127.6.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klymkowsky M. W., Parr B. The body language of cells: the intimate connection between cell adhesion and behavior. Cell. 1995 Oct 6;83(1):5–8. doi: 10.1016/0092-8674(95)90226-0. [DOI] [PubMed] [Google Scholar]
  16. Liao G., Nagasaki T., Gundersen G. G. Low concentrations of nocodazole interfere with fibroblast locomotion without significantly affecting microtubule level: implications for the role of dynamic microtubules in cell locomotion. J Cell Sci. 1995 Nov;108(Pt 11):3473–3483. doi: 10.1242/jcs.108.11.3473. [DOI] [PubMed] [Google Scholar]
  17. Matsumine A., Ogai A., Senda T., Okumura N., Satoh K., Baeg G. H., Kawahara T., Kobayashi S., Okada M., Toyoshima K. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science. 1996 May 17;272(5264):1020–1023. doi: 10.1126/science.272.5264.1020. [DOI] [PubMed] [Google Scholar]
  18. McLean I. W., Nakane P. K. Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem. 1974 Dec;22(12):1077–1083. doi: 10.1177/22.12.1077. [DOI] [PubMed] [Google Scholar]
  19. McNeill H., Ryan T. A., Smith S. J., Nelson W. J. Spatial and temporal dissection of immediate and early events following cadherin-mediated epithelial cell adhesion. J Cell Biol. 1993 Mar;120(5):1217–1226. doi: 10.1083/jcb.120.5.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Munemitsu S., Albert I., Souza B., Rubinfeld B., Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3046–3050. doi: 10.1073/pnas.92.7.3046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Munemitsu S., Souza B., Müller O., Albert I., Rubinfeld B., Polakis P. The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res. 1994 Jul 15;54(14):3676–3681. [PubMed] [Google Scholar]
  22. Näthke I. S., Hinck L., Swedlow J. R., Papkoff J., Nelson W. J. Defining interactions and distributions of cadherin and catenin complexes in polarized epithelial cells. J Cell Biol. 1994 Jun;125(6):1341–1352. doi: 10.1083/jcb.125.6.1341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ozawa M., Ringwald M., Kemler R. Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4246–4250. doi: 10.1073/pnas.87.11.4246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Polakis P. Mutations in the APC gene and their implications for protein structure and function. Curr Opin Genet Dev. 1995 Feb;5(1):66–71. doi: 10.1016/s0959-437x(95)90055-1. [DOI] [PubMed] [Google Scholar]
  25. Quaroni A., Wands J., Trelstad R. L., Isselbacher K. J. Epithelioid cell cultures from rat small intestine. Characterization by morphologic and immunologic criteria. J Cell Biol. 1979 Feb;80(2):248–265. doi: 10.1083/jcb.80.2.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rimm D. L., Koslov E. R., Kebriaei P., Cianci C. D., Morrow J. S. Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8813–8817. doi: 10.1073/pnas.92.19.8813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rubinfeld B., Souza B., Albert I., Munemitsu S., Polakis P. The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin. J Biol Chem. 1995 Mar 10;270(10):5549–5555. doi: 10.1074/jbc.270.10.5549. [DOI] [PubMed] [Google Scholar]
  28. Rubinfeld B., Souza B., Albert I., Müller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. doi: 10.1126/science.8259518. [DOI] [PubMed] [Google Scholar]
  29. Sabry J. H., O'Connor T. P., Evans L., Toroian-Raymond A., Kirschner M., Bentley D. Microtubule behavior during guidance of pioneer neuron growth cones in situ. J Cell Biol. 1991 Oct;115(2):381–395. doi: 10.1083/jcb.115.2.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Smith K. J., Levy D. B., Maupin P., Pollard T. D., Vogelstein B., Kinzler K. W. Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 1994 Jul 15;54(14):3672–3675. [PubMed] [Google Scholar]
  31. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. doi: 10.1126/science.8259519. [DOI] [PubMed] [Google Scholar]
  32. Tanaka E., Ho T., Kirschner M. W. The role of microtubule dynamics in growth cone motility and axonal growth. J Cell Biol. 1995 Jan;128(1-2):139–155. doi: 10.1083/jcb.128.1.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tanaka E., Sabry J. Making the connection: cytoskeletal rearrangements during growth cone guidance. Cell. 1995 Oct 20;83(2):171–176. doi: 10.1016/0092-8674(95)90158-2. [DOI] [PubMed] [Google Scholar]
  34. Vale R. D., Malik F., Brown D. Directional instability of microtubule transport in the presence of kinesin and dynein, two opposite polarity motor proteins. J Cell Biol. 1992 Dec;119(6):1589–1596. doi: 10.1083/jcb.119.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watabe M., Matsumoto K., Nakamura T., Takeichi M. Effect of hepatocyte growth factor on cadherin-mediated cell-cell adhesion. Cell Struct Funct. 1993 Apr;18(2):117–124. doi: 10.1247/csf.18.117. [DOI] [PubMed] [Google Scholar]
  36. Zarnegar R., Michalopoulos G. K. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol. 1995 Jun;129(5):1177–1180. doi: 10.1083/jcb.129.5.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES