Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1995 Jun 15;14(12):2827–2838. doi: 10.1002/j.1460-2075.1995.tb07282.x

The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions.

C Serra-Pagès 1, N L Kedersha 1, L Fazikas 1, Q Medley 1, A Debant 1, M Streuli 1
PMCID: PMC398401  PMID: 7796809

Abstract

Focal adhesions are sites of cell-extracellular matrix interactions that function in anchoring stress fibers to the plasma membrane and in adhesion-mediated signal transduction. Both focal adhesion structure and signaling ability involve protein tyrosine phosphorylation. LAR is a broadly expressed transmembrane protein tyrosine phosphatase comprised of a cell adhesion-like ectodomain and two intracellular protein tyrosine phosphatase domains. We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions. Both LAR and LIP.1 decorate the ends of focal adhesions most proximal to the cell nucleus and are excluded from the distal ends of focal adhesions, thus localizing to regions of focal adhesions presumably undergoing disassembly. We propose that LAR and LIP.1 may regulate the disassembly of focal adhesions and thus help orchestrate cell-matrix interactions.

Full text

PDF
2827

Images in this article

2828Image
on p.2828
2829Image
on p.2829
2831Image
on p.2831
2832Image
on p.2832
2834Image
on p.2834

Selected References

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

  1. Bennett P. A., Dixon R. J., Kellie S. The phosphotyrosine phosphatase inhibitor vanadyl hydroperoxide induces morphological alterations, cytoskeletal rearrangements and increased adhesiveness in rat neutrophil leucocytes. J Cell Sci. 1993 Nov;106(Pt 3):891–901. doi: 10.1242/jcs.106.3.891. [DOI] [PubMed] [Google Scholar]
  2. Bockholt S. M., Burridge K. Cell spreading on extracellular matrix proteins induces tyrosine phosphorylation of tensin. J Biol Chem. 1993 Jul 15;268(20):14565–14567. [PubMed] [Google Scholar]
  3. Bonthron D. T., Handin R. I., Kaufman R. J., Wasley L. C., Orr E. C., Mitsock L. M., Ewenstein B., Loscalzo J., Ginsburg D., Orkin S. H. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature. 1986 Nov 20;324(6094):270–273. doi: 10.1038/324270a0. [DOI] [PubMed] [Google Scholar]
  4. Boyle W. J., van der Geer P., Hunter T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 1991;201:110–149. doi: 10.1016/0076-6879(91)01013-r. [DOI] [PubMed] [Google Scholar]
  5. Brady-Kalnay S. M., Flint A. J., Tonks N. K. Homophilic binding of PTP mu, a receptor-type protein tyrosine phosphatase, can mediate cell-cell aggregation. J Cell Biol. 1993 Aug;122(4):961–972. doi: 10.1083/jcb.122.4.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brady-Kalnay S. M., Tonks N. K. Identification of the homophilic binding site of the receptor protein tyrosine phosphatase PTP mu. J Biol Chem. 1994 Nov 11;269(45):28472–28477. [PubMed] [Google Scholar]
  7. Burridge K., Fath K., Kelly T., Nuckolls G., Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol. 1988;4:487–525. doi: 10.1146/annurev.cb.04.110188.002415. [DOI] [PubMed] [Google Scholar]
  8. Burridge K., Turner C. E., Romer L. H. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992 Nov;119(4):893–903. doi: 10.1083/jcb.119.4.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen H. C., Guan J. L. Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10148–10152. doi: 10.1073/pnas.91.21.10148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chien C. T., Bartel P. L., Sternglanz R., Fields S. The two-hybrid system: a method to identify and clone genes for proteins that interact with a protein of interest. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9578–9582. doi: 10.1073/pnas.88.21.9578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dunlevy J. R., Couchman J. R. Controlled induction of focal adhesion disassembly and migration in primary fibroblasts. J Cell Sci. 1993 Jun;105(Pt 2):489–500. doi: 10.1242/jcs.105.2.489. [DOI] [PubMed] [Google Scholar]
  12. Fischer E. H., Charbonneau H., Tonks N. K. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991 Jul 26;253(5018):401–406. doi: 10.1126/science.1650499. [DOI] [PubMed] [Google Scholar]
  13. Frangioni J. V., Beahm P. H., Shifrin V., Jost C. A., Neel B. G. The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell. 1992 Feb 7;68(3):545–560. doi: 10.1016/0092-8674(92)90190-n. [DOI] [PubMed] [Google Scholar]
  14. Gates R. E., Hanks S. K., King L. E., Jr Focal-adhesion components are enriched in ventral membranes isolated from transformed keratinocytes in culture. Biochem J. 1993 Jan 1;289(Pt 1):221–226. doi: 10.1042/bj2890221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gautier J., Solomon M. J., Booher R. N., Bazan J. F., Kirschner M. W. cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell. 1991 Oct 4;67(1):197–211. doi: 10.1016/0092-8674(91)90583-k. [DOI] [PubMed] [Google Scholar]
  16. Glenney J. R., Jr, Zokas L. Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton. J Cell Biol. 1989 Jun;108(6):2401–2408. doi: 10.1083/jcb.108.6.2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Guan J. L., Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature. 1992 Aug 20;358(6388):690–692. doi: 10.1038/358690a0. [DOI] [PubMed] [Google Scholar]
  18. Guan J. L., Trevithick J. E., Hynes R. O. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Regul. 1991 Nov;2(11):951–964. doi: 10.1091/mbc.2.11.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gyuris J., Golemis E., Chertkov H., Brent R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell. 1993 Nov 19;75(4):791–803. doi: 10.1016/0092-8674(93)90498-f. [DOI] [PubMed] [Google Scholar]
  20. Hynes R. O., Lander A. D. Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell. 1992 Jan 24;68(2):303–322. doi: 10.1016/0092-8674(92)90472-o. [DOI] [PubMed] [Google Scholar]
  21. Jaken S., Leach K., Klauck T. Association of type 3 protein kinase C with focal contacts in rat embryo fibroblasts. J Cell Biol. 1989 Aug;109(2):697–704. doi: 10.1083/jcb.109.2.697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kaplan K. B., Bibbins K. B., Swedlow J. R., Arnaud M., Morgan D. O., Varmus H. E. Association of the amino-terminal half of c-Src with focal adhesions alters their properties and is regulated by phosphorylation of tyrosine 527. EMBO J. 1994 Oct 17;13(20):4745–4756. doi: 10.1002/j.1460-2075.1994.tb06800.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kinzler K. W., Nilbert M. C., Su L. K., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hedge P., McKechnie D. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. doi: 10.1126/science.1651562. [DOI] [PubMed] [Google Scholar]
  24. Kishihara K., Penninger J., Wallace V. A., Kündig T. M., Kawai K., Wakeham A., Timms E., Pfeffer K., Ohashi P. S., Thomas M. L. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell. 1993 Jul 16;74(1):143–156. doi: 10.1016/0092-8674(93)90302-7. [DOI] [PubMed] [Google Scholar]
  25. Kornberg L., Earp H. S., Parsons J. T., Schaller M., Juliano R. L. Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem. 1992 Nov 25;267(33):23439–23442. [PubMed] [Google Scholar]
  26. Li W., Nishimura R., Kashishian A., Batzer A. G., Kim W. J., Cooper J. A., Schlessinger J. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994 Jan;14(1):509–517. doi: 10.1128/mcb.14.1.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lipfert L., Haimovich B., Schaller M. D., Cobb B. S., Parsons J. T., Brugge J. S. Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J Cell Biol. 1992 Nov;119(4):905–912. doi: 10.1083/jcb.119.4.905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lo S. H., Chen L. B. Focal adhesion as a signal transduction organelle. Cancer Metastasis Rev. 1994 Mar;13(1):9–24. doi: 10.1007/BF00690415. [DOI] [PubMed] [Google Scholar]
  29. Lupas A., Van Dyke M., Stock J. Predicting coiled coils from protein sequences. Science. 1991 May 24;252(5009):1162–1164. doi: 10.1126/science.252.5009.1162. [DOI] [PubMed] [Google Scholar]
  30. Maher P. A., Pasquale E. B., Wang J. Y., Singer S. J. Phosphotyrosine-containing proteins are concentrated in focal adhesions and intercellular junctions in normal cells. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6576–6580. doi: 10.1073/pnas.82.19.6576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Matthews R. J., Bowne D. B., Flores E., Thomas M. L. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Mol Cell Biol. 1992 May;12(5):2396–2405. doi: 10.1128/mcb.12.5.2396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mueller S. C., Yeh Y., Chen W. T. Tyrosine phosphorylation of membrane proteins mediates cellular invasion by transformed cells. J Cell Biol. 1992 Dec;119(5):1309–1325. doi: 10.1083/jcb.119.5.1309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. O'Grady P., Krueger N. X., Streuli M., Saito H. Genomic organization of the human LAR protein tyrosine phosphatase gene and alternative splicing in the extracellular fibronectin type-III domains. J Biol Chem. 1994 Oct 7;269(40):25193–25199. [PubMed] [Google Scholar]
  34. Perkins L. A., Larsen I., Perrimon N. corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell. 1992 Jul 24;70(2):225–236. doi: 10.1016/0092-8674(92)90098-w. [DOI] [PubMed] [Google Scholar]
  35. Pulido R., Krueger N. X., Serra-Pagès C., Saito H., Streuli M. Molecular characterization of the human transmembrane protein-tyrosine phosphatase delta. Evidence for tissue-specific expression of alternative human transmembrane protein-tyrosine phosphatase delta isoforms. J Biol Chem. 1995 Mar 24;270(12):6722–6728. doi: 10.1074/jbc.270.12.6722. [DOI] [PubMed] [Google Scholar]
  36. Ridley A. J., Hall A. Signal transduction pathways regulating Rho-mediated stress fibre formation: requirement for a tyrosine kinase. EMBO J. 1994 Jun 1;13(11):2600–2610. doi: 10.1002/j.1460-2075.1994.tb06550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ridley A. J., Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992 Aug 7;70(3):389–399. doi: 10.1016/0092-8674(92)90163-7. [DOI] [PubMed] [Google Scholar]
  38. Saito H., Streuli M. Molecular characterization of protein tyrosine phosphatases. Cell Growth Differ. 1991 Jan;2(1):59–65. [PubMed] [Google Scholar]
  39. Sap J., Jiang Y. P., Friedlander D., Grumet M., Schlessinger J. Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol. 1994 Jan;14(1):1–9. doi: 10.1128/mcb.14.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schaller M. D., Borgman C. A., Cobb B. S., Vines R. R., Reynolds A. B., Parsons J. T. pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5192–5196. doi: 10.1073/pnas.89.11.5192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schlaepfer D. D., Hanks S. K., Hunter T., van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994 Dec 22;372(6508):786–791. doi: 10.1038/372786a0. [DOI] [PubMed] [Google Scholar]
  42. Schlessinger J., Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992 Sep;9(3):383–391. doi: 10.1016/0896-6273(92)90177-f. [DOI] [PubMed] [Google Scholar]
  43. Schneider G., Burridge K. Formation of focal adhesions by osteoblasts adhering to different substrata. Exp Cell Res. 1994 Sep;214(1):264–269. doi: 10.1006/excr.1994.1257. [DOI] [PubMed] [Google Scholar]
  44. Serra-Pages C., Saito H., Streuli M. Mutational analysis of proprotein processing, subunit association, and shedding of the LAR transmembrane protein tyrosine phosphatase. J Biol Chem. 1994 Sep 23;269(38):23632–23641. [PubMed] [Google Scholar]
  45. Shultz L. D., Schweitzer P. A., Rajan T. V., Yi T., Ihle J. N., Matthews R. J., Thomas M. L., Beier D. R. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993 Jul 2;73(7):1445–1454. doi: 10.1016/0092-8674(93)90369-2. [DOI] [PubMed] [Google Scholar]
  46. Sonderegger P., Rathjen F. G. Regulation of axonal growth in the vertebrate nervous system by interactions between glycoproteins belonging to two subgroups of the immunoglobulin superfamily. J Cell Biol. 1992 Dec;119(6):1387–1394. doi: 10.1083/jcb.119.6.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Stetler-Stevenson W. G., Aznavoorian S., Liotta L. A. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol. 1993;9:541–573. doi: 10.1146/annurev.cb.09.110193.002545. [DOI] [PubMed] [Google Scholar]
  48. Streuli M., Krueger N. X., Ariniello P. D., Tang M., Munro J. M., Blattler W. A., Adler D. A., Disteche C. M., Saito H. Expression of the receptor-linked protein tyrosine phosphatase LAR: proteolytic cleavage and shedding of the CAM-like extracellular region. EMBO J. 1992 Mar;11(3):897–907. doi: 10.1002/j.1460-2075.1992.tb05128.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Streuli M., Krueger N. X., Hall L. R., Schlossman S. F., Saito H. A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to the leukocyte common antigen. J Exp Med. 1988 Nov 1;168(5):1523–1530. doi: 10.1084/jem.168.5.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Su L. K., Johnson K. A., Smith K. J., Hill D. E., Vogelstein B., Kinzler K. W. Association between wild type and mutant APC gene products. Cancer Res. 1993 Jun 15;53(12):2728–2731. [PubMed] [Google Scholar]
  51. 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]
  52. Sun H., Charles C. H., Lau L. F., Tonks N. K. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993 Nov 5;75(3):487–493. doi: 10.1016/0092-8674(93)90383-2. [DOI] [PubMed] [Google Scholar]
  53. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Trowbridge I. S., Thomas M. L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu Rev Immunol. 1994;12:85–116. doi: 10.1146/annurev.iy.12.040194.000505. [DOI] [PubMed] [Google Scholar]
  55. Vogel W., Lammers R., Huang J., Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993 Mar 12;259(5101):1611–1614. doi: 10.1126/science.7681217. [DOI] [PubMed] [Google Scholar]
  56. Volberg T., Zick Y., Dror R., Sabanay I., Gilon C., Levitzki A., Geiger B. The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions. EMBO J. 1992 May;11(5):1733–1742. doi: 10.1002/j.1460-2075.1992.tb05225.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Williams A. F., Barclay A. N. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol. 1988;6:381–405. doi: 10.1146/annurev.iy.06.040188.002121. [DOI] [PubMed] [Google Scholar]
  58. Yan H., Grossman A., Wang H., D'Eustachio P., Mossie K., Musacchio J. M., Silvennoinen O., Schlessinger J. A novel receptor tyrosine phosphatase-sigma that is highly expressed in the nervous system. J Biol Chem. 1993 Nov 25;268(33):24880–24886. [PubMed] [Google Scholar]
  59. Yang Q., Tonks N. K. Isolation of a cDNA clone encoding a human protein-tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4.1, ezrin, and talin. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):5949–5953. doi: 10.1073/pnas.88.14.5949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yu Q., Lenardo T., Weinberg R. A. The N-terminal and C-terminal domains of a receptor tyrosine phosphatase are associated by non-covalent linkage. Oncogene. 1992 Jun;7(6):1051–1057. [PubMed] [Google Scholar]
  61. Zachary I., Sinnett-Smith J., Turner C. E., Rozengurt E. Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation of the focal adhesion-associated protein paxillin in Swiss 3T3 cells. J Biol Chem. 1993 Oct 15;268(29):22060–22065. [PubMed] [Google Scholar]
  62. Zhang J. S., Longo F. M. LAR tyrosine phosphatase receptor: alternative splicing is preferential to the nervous system, coordinated with cell growth and generates novel isoforms containing extensive CAG repeats. J Cell Biol. 1995 Feb;128(3):415–431. doi: 10.1083/jcb.128.3.415. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES