Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Jul 15;365(Pt 2):513–519. doi: 10.1042/BJ20020381

Expression of the leucocyte common antigen-related (LAR) tyrosine phosphatase is regulated by cell density through functional E-cadherin complexes.

Javelle R Symons 1, Charles M LeVea 1, Robert A Mooney 1
PMCID: PMC1222702  PMID: 12095414

Abstract

The leucocyte common antigen-related phosphatase (LAR) has been implicated in receptor tyrosine kinase signalling pathways while also displaying cell-density-dependency and localization to adherens junctions. Whereas physiological substrates for LAR have not been identified unequivocally, beta-catenin associates with LAR and is a substrate in vitro. With the implication that LAR may play a role in regulating E-cadherin-dependent cell-cell communication and contact inhibition, the relationship of LAR with E-cadherin was investigated. LAR expression increased with cell density in the human breast cancer cell line MCF-7 and in Ln 3 cells derived from the 13762NF rat mammary adenocarcinoma. LAR protein levels decreased rapidly when cells were replated at a low density after attaining high expression of LAR at high cell density. COS-7 cells displayed comparable density-dependent regulation of LAR expression when transiently expressing exogenous LAR under the control of a constitutively active promoter, indicating that the regulation of expression is not at the level of gene regulation. Disrupting homophilic E-cadherin complexes by chelating extracellular calcium caused a marked decrease in LAR protein levels. Similarly, blocking E-cadherin interactions with saturating amounts of E-cadherin antibody (HECD-1) also led to a rapid and pronounced loss of cellular LAR. In contrast, mimicking cell-surface E-cadherin engagement by plating cells at low density on to dishes coated with HECD-1 resulted in a 2-fold increase in LAR expression compared with controls. These results suggest that density-dependent regulation of LAR expression is mediated by functional E-cadherin and may play a role in density-dependent contact inhibition by regulating tyrosine phosphorylation in E-cadherin complexes.

Full Text

The Full Text of this article is available as a PDF (187.6 KB).

Selected References

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

  1. Aicher B., Lerch M. M., Müller T., Schilling J., Ullrich A. Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing. J Cell Biol. 1997 Aug 11;138(3):681–696. doi: 10.1083/jcb.138.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balsamo J., Leung T., Ernst H., Zanin M. K., Hoffman S., Lilien J. Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of beta-catenin. J Cell Biol. 1996 Aug;134(3):801–813. doi: 10.1083/jcb.134.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Bleyle L. A., Peng Y., Ellis C., Mooney R. A. Dissociation of PTPase levels from their modulation of insulin receptor signal transduction. Cell Signal. 1999 Oct;11(10):719–725. doi: 10.1016/s0898-6568(99)00043-1. [DOI] [PubMed] [Google Scholar]
  5. Brady-Kalnay S. M., Rimm D. L., Tonks N. K. Receptor protein tyrosine phosphatase PTPmu associates with cadherins and catenins in vivo. J Cell Biol. 1995 Aug;130(4):977–986. doi: 10.1083/jcb.130.4.977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bukholm I. K., Nesland J. M., Kåresen R., Jacobsen U., Børresen-Dale A. L. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol. 1998 Jul;185(3):262–266. doi: 10.1002/(SICI)1096-9896(199807)185:3<262::AID-PATH97>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  7. Gebbink M. F., Zondag G. C., Koningstein G. M., Feiken E., Wubbolts R. W., Moolenaar W. H. Cell surface expression of receptor protein tyrosine phosphatase RPTP mu is regulated by cell-cell contact. J Cell Biol. 1995 Oct;131(1):251–260. doi: 10.1083/jcb.131.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gumbiner B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996 Feb 9;84(3):345–357. doi: 10.1016/s0092-8674(00)81279-9. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Hiscox S., Jiang W. G. Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. Biochem Biophys Res Commun. 1999 Aug 2;261(2):406–411. doi: 10.1006/bbrc.1999.1002. [DOI] [PubMed] [Google Scholar]
  11. Hiscox S., Jiang W. G. Hepatocyte growth factor/scatter factor disrupts epithelial tumour cell-cell adhesion: involvement of beta-catenin. Anticancer Res. 1999 Jan-Feb;19(1A):509–517. [PubMed] [Google Scholar]
  12. Kanner S. B., Reynolds A. B., Parsons J. T. Tyrosine phosphorylation of a 120-kilodalton pp60src substrate upon epidermal growth factor and platelet-derived growth factor receptor stimulation and in polyomavirus middle-T-antigen-transformed cells. Mol Cell Biol. 1991 Feb;11(2):713–720. doi: 10.1128/mcb.11.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Keilhack H., Hellman U., van Hengel J., van Roy F., Godovac-Zimmermann J., Böhmer F. D. The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin. J Biol Chem. 2000 Aug 25;275(34):26376–26384. doi: 10.1074/jbc.M001315200. [DOI] [PubMed] [Google Scholar]
  14. Kinch M. S., Clark G. J., Der C. J., Burridge K. Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia. J Cell Biol. 1995 Jul;130(2):461–471. doi: 10.1083/jcb.130.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kypta R. M., Su H., Reichardt L. F. Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J Cell Biol. 1996 Sep;134(6):1519–1529. doi: 10.1083/jcb.134.6.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lambert M., Padilla F., Mège R. M. Immobilized dimers of N-cadherin-Fc chimera mimic cadherin-mediated cell contact formation: contribution of both outside-in and inside-out signals. J Cell Sci. 2000 Jun;113(Pt 12):2207–2219. doi: 10.1242/jcs.113.12.2207. [DOI] [PubMed] [Google Scholar]
  17. Mareel M., Bracke M., Van Roy F. Invasion promoter versus invasion suppressor molecules: the paradigm of E-cadherin. Mol Biol Rep. 1994 Jan;19(1):45–67. doi: 10.1007/BF00987321. [DOI] [PubMed] [Google Scholar]
  18. Matsuyoshi N., Hamaguchi M., Taniguchi S., Nagafuchi A., Tsukita S., Takeichi M. Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts. J Cell Biol. 1992 Aug;118(3):703–714. doi: 10.1083/jcb.118.3.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Müller T., Choidas A., Reichmann E., Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. J Biol Chem. 1999 Apr 9;274(15):10173–10183. doi: 10.1074/jbc.274.15.10173. [DOI] [PubMed] [Google Scholar]
  20. Nagafuchi A., Ishihara S., Tsukita S. The roles of catenins in the cadherin-mediated cell adhesion: functional analysis of E-cadherin-alpha catenin fusion molecules. J Cell Biol. 1994 Oct;127(1):235–245. doi: 10.1083/jcb.127.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Neri A., Welch D., Kawaguchi T., Nicolson G. L. Development and biologic properties of malignant cell sublines and clones of a spontaneously metastasizing rat mammary adenocarcinoma. J Natl Cancer Inst. 1982 Mar;68(3):507–517. [PubMed] [Google Scholar]
  22. Nose A., Nagafuchi A., Takeichi M. Expressed recombinant cadherins mediate cell sorting in model systems. Cell. 1988 Sep 23;54(7):993–1001. doi: 10.1016/0092-8674(88)90114-6. [DOI] [PubMed] [Google Scholar]
  23. O'Grady P., Thai T. C., Saito H. The laminin-nidogen complex is a ligand for a specific splice isoform of the transmembrane protein tyrosine phosphatase LAR. J Cell Biol. 1998 Jun 29;141(7):1675–1684. doi: 10.1083/jcb.141.7.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ostman A., Yang Q., Tonks N. K. Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9680–9684. doi: 10.1073/pnas.91.21.9680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ozawa M., Kemler R. Altered cell adhesion activity by pervanadate due to the dissociation of alpha-catenin from the E-cadherin.catenin complex. J Biol Chem. 1998 Mar 13;273(11):6166–6170. doi: 10.1074/jbc.273.11.6166. [DOI] [PubMed] [Google Scholar]
  26. Papkoff J. Regulation of complexed and free catenin pools by distinct mechanisms. Differential effects of Wnt-1 and v-Src. J Biol Chem. 1997 Feb 14;272(7):4536–4543. [PubMed] [Google Scholar]
  27. Rahimi N., Hung W., Tremblay E., Saulnier R., Elliott B. c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem. 1998 Dec 11;273(50):33714–33721. doi: 10.1074/jbc.273.50.33714. [DOI] [PubMed] [Google Scholar]
  28. Schaapveld R. Q., Schepens J. T., Robinson G. W., Attema J., Oerlemans F. T., Fransen J. A., Streuli M., Wieringa B., Hennighausen L., Hendriks W. J. Impaired mammary gland development and function in mice lacking LAR receptor-like tyrosine phosphatase activity. Dev Biol. 1997 Aug 1;188(1):134–146. doi: 10.1006/dbio.1997.8630. [DOI] [PubMed] [Google Scholar]
  29. Shibata T., Ochiai A., Kanai Y., Akimoto S., Gotoh M., Yasui N., Machinami R., Hirohashi S. Dominant negative inhibition of the association between beta-catenin and c-erbB-2 by N-terminally deleted beta-catenin suppresses the invasion and metastasis of cancer cells. Oncogene. 1996 Sep 5;13(5):883–889. [PubMed] [Google Scholar]
  30. Shiozaki H., Oka H., Inoue M., Tamura S., Monden M. E-cadherin mediated adhesion system in cancer cells. Cancer. 1996 Apr 15;77(8 Suppl):1605–1613. doi: 10.1002/(SICI)1097-0142(19960415)77:8<1605::AID-CNCR28>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  31. Takahashi K., Suzuki K., Tsukatani Y. Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence. Oncogene. 1997 Jul 3;15(1):71–78. doi: 10.1038/sj.onc.1201160. [DOI] [PubMed] [Google Scholar]
  32. Ukropec J. A., Hollinger M. K., Salva S. M., Woolkalis M. J. SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin. J Biol Chem. 2000 Feb 25;275(8):5983–5986. doi: 10.1074/jbc.275.8.5983. [DOI] [PubMed] [Google Scholar]
  33. Vleminckx K., Kemler R. Cadherins and tissue formation: integrating adhesion and signaling. Bioessays. 1999 Mar;21(3):211–220. doi: 10.1002/(SICI)1521-1878(199903)21:3<211::AID-BIES5>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]
  34. Weng L. P., Yuan J., Yu Q. Overexpression of the transmembrane tyrosine phosphatase LAR activates the caspase pathway and induces apoptosis. Curr Biol. 1998 Feb 26;8(5):247–256. doi: 10.1016/s0960-9822(98)70106-x. [DOI] [PubMed] [Google Scholar]
  35. Xu Y., Carpenter G. Identification of cadherin tyrosine residues that are phosphorylated and mediate Shc association. J Cell Biochem. 1999 Nov 1;75(2):264–271. doi: 10.1002/(sici)1097-4644(19991101)75:2<264::aid-jcb9>3.3.co;2-2. [DOI] [PubMed] [Google Scholar]
  36. Zhai Y., Wirth J., Kang S., Welsch C. W., Esselman W. J. LAR-PTPase cDNA transfection suppression of tumor growth of neu oncogene-transformed human breast carcinoma cells. Mol Carcinog. 1995 Oct;14(2):103–110. doi: 10.1002/mc.2940140206. [DOI] [PubMed] [Google Scholar]
  37. Zhang JS, Honkaniemi J, Yang T, Yeo TT, Longo FM. LAR Tyrosine Phosphatase Receptor: A Developmental Isoform Is Present in Neurites and Growth Cones and Its Expression Is Regional- and Cell-Specific. Mol Cell Neurosci. 1998 Apr;10(5/6):271–286. doi: 10.1006/mcne.1998.0663. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES