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PMID: 11154277 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Gas6 induces growth, beta-catenin stabilization, and T-cell factor transcriptional activation in contact-inhibited C57 mammary cells.

Molecular and cellular biology ·Vol. 21 ·No. 3 ·2001-02-00 ·Pages 902-15

Goruppi S, Chiaruttini C, Ruaro ME, Varnum B, Schneider C

Abstract

Gas6 is a growth factor related to protein S that was identified as the ligand for the Axl receptor tyrosine kinase (RTK) family. In this study, we show that Gas6 induces a growth response in a cultured mammalian mammary cell line, C57MG. The presence of Gas6 in the medium induces growth after confluence and similarly causes cell cycle reentry of density-inhibited C57MG cells. We show that Axl RTK but not Rse is efficiently activated by Gas6 in density-inhibited C57MG cells. We have analyzed the signaling required for the Gas6 proliferative effect and found a requirement for PI3K-, S6K-, and Ras-activated pathways. We also demonstrate that Gas6 activates Akt and concomitantly inhibits GSK3 activity in a wortmannin-dependent manner. Interestingly, Gas6 induces up-regulation of cytosolic beta-catenin, while membrane-associated beta-catenin remains unaffected. Stabilization of beta-catenin in C57MG cells is correlated with activation of a T-cell factor (TCF)-responsive transcriptional element. We thus provide evidence that Gas6 is mitogenic and induces beta-catenin proto-oncogene stabilization and subsequent TCF/Lef transcriptional activation in a mammary system. These results suggest that Gas6-Axl interaction, through stabilization of beta-catenin, may have a role in mammary development and/or be involved in the progression of mammary tumors.

MeSH Terms
3T3 Cells Animals Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Count Cell Division/drug effects Cell Line Contact Inhibition Cytoskeletal Proteins/metabolism Female Glycogen Synthase Kinase 3 Humans Intercellular Signaling Peptides and Proteins Mammary Glands, Animal/cytology,drug effects,metabolism Mice Oncogene Proteins/metabolism Proteins/pharmacology Proto-Oncogene Mas Proto-Oncogene Proteins Rats Receptor Protein-Tyrosine Kinases/metabolism TCF Transcription Factors Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors/genetics Transcriptional Activation/drug effects beta Catenin
Chemicals
CTNNB1 protein, human CTNNB1 protein, mouse Ctnnb1 protein, rat Cytoskeletal Proteins Intercellular Signaling Peptides and Proteins MAS1 protein, human Oncogene Proteins Proteins Proto-Oncogene Mas Proto-Oncogene Proteins TCF Transcription Factors TCF7L2 protein, human Tcf7l2 protein, mouse Tcf7l2 protein, rat Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors beta Catenin growth arrest-specific protein 6 Receptor Protein-Tyrosine Kinases axl receptor tyrosine kinase Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Goruppi S
LNCIB (Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie), 34012 Trieste, Italy.
Chiaruttini C
Ruaro M E
Varnum B
Schneider C
References (93)
93 references, click to expand
  1. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway.
    Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7 PMID: 10318916
  2. bFGF inhibits the activation of caspase-3 and apoptosis of P19 embryonal carcinoma cells during neuronal differentiation.
    Cell Death Differ. 1999 May;6(5):463-70 PMID: 10381633
  3. Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras.
    Oncogene. 1999 Jul 22;18(29):4224-36 PMID: 10435635
  4. Exogenous expression of beta-catenin regulates contact inhibition, anchorage-independent growth, anoikis, and radiation-induced cell cycle arrest.
    J Cell Biol. 1999 Aug 23;146(4):855-68 PMID: 10459019
  5. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.
    Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10182-7 PMID: 10468583
  6. H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.
    J Cell Biol. 1999 Sep 6;146(5):967-80 PMID: 10477752
  7. The mouse Wnt-1 gene can act via a paracrine mechanism in transformation of mammary epithelial cells.
    Mol Cell Biol. 1992 Jan;12(1):321-8 PMID: 1530877
  8. Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (uvomorulin). Characterization and extractability of the protein complex from the cell cytostructure.
    J Biol Chem. 1991 Mar 5;266(7):4514-20 PMID: 1999432
  9. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system.
    Neuron. 1991 May;6(5):691-704 PMID: 2025425
  10. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.
    Mol Cell Biol. 1991 Oct;11(10):5016-31 PMID: 1656220
  11. A putative receptor tyrosine kinase with unique structural topology.
    Oncogene. 1991 Oct;6(10):1909-13 PMID: 1840679
  12. A novel putative tyrosine kinase receptor with oncogenic potential.
    Oncogene. 1991 Nov;6(11):2113-20 PMID: 1834974
  13. The biochemical properties and transforming potential of human Wnt-2 are similar to Wnt-1.
    Oncogene. 1992 Jan;7(1):153-61 PMID: 1371336
  14. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases.
    Cell. 1992 Jun 26;69(7):1227-36 PMID: 1377606
  15. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B.
    Biochem J. 1993 Sep 15;294 ( Pt 3):625-9 PMID: 8397507
  16. Association of the APC gene product with beta-catenin.
    Science. 1993 Dec 10;262(5140):1731-4 PMID: 8259518
  17. Association of the APC tumor suppressor protein with catenins.
    Science. 1993 Dec 10;262(5140):1734-7 PMID: 8259519
  18. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6.
    Nature. 1995 Feb 16;373(6515):623-6 PMID: 7854420
  19. Vascular smooth muscle cell-derived, Gla-containing growth-potentiating factor for Ca(2+)-mobilizing growth factors.
    J Biol Chem. 1995 Mar 17;270(11):5702-5 PMID: 7890695
  20. pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila.
    Nature. 1997 Feb 27;385(6619):829-33 PMID: 9039917
  21. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma.
    Science. 1997 Mar 21;275(5307):1784-7 PMID: 9065401
  22. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
    Science. 1997 Mar 21;275(5307):1787-90 PMID: 9065402
  23. Stabilization of beta-catenin by genetic defects in melanoma cell lines.
    Science. 1997 Mar 21;275(5307):1790-2 PMID: 9065403
  24. Beta-catenin as oncogene: the smoking gun.
    Science. 1997 Mar 21;275(5307):1752-3 PMID: 9122680
  25. A versatile transcriptional effector of Wingless signaling.
    Cell. 1997 May 2;89(3):321-3 PMID: 9150130
  26. Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation.
    Oncogene. 1997 May 1;14(17):2033-9 PMID: 9160883
  27. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
    Cell. 1997 Oct 17;91(2):231-41 PMID: 9346240
  28. Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation.
    Oncogene. 1997 Nov 13;15(20):2387-97 PMID: 9395235
  29. Transformation by Wnt family proteins correlates with regulation of beta-catenin.
    Cell Growth Differ. 1997 Dec;8(12):1349-58 PMID: 9419423
  30. Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts.
    J Cell Biol. 1992 Aug;118(3):703-14 PMID: 1639852
  31. The growth arrest-specific gene, gas1, is involved in growth suppression.
    Cell. 1992 Aug 21;70(4):595-607 PMID: 1505026
  32. 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):757-66 PMID: 8425900
  33. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade.
    Mol Cell Biol. 1993 Aug;13(8):4976-85 PMID: 8336730
  34. The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains.
    J Biol Chem. 1994 Jan 21;269(3):1839-44 PMID: 7507487
  35. Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain.
    Oncogene. 1994 Mar;9(3):699-705 PMID: 8108112
  36. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly.
    J Cell Biol. 1994 Jun;125(6):1327-40 PMID: 8207061
  37. Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase.
    Oncogene. 1994 Sep;9(9):2567-78 PMID: 8058320
  38. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer.
    Cell Growth Differ. 1994 Jun;5(6):647-57 PMID: 8086340
  39. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf.
    Biochem J. 1994 Oct 1;303 ( Pt 1):21-6 PMID: 7945242
  40. The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells.
    Biochem J. 1994 Oct 1;303 ( Pt 1):27-31 PMID: 7945252
  41. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation.
    Biochem J. 1994 Nov 1;303 ( Pt 3):701-4 PMID: 7980435
  42. Oncogenes and the strategy of growth factors.
    Cell. 1994 Dec 16;79(6):927-30 PMID: 8001140
  43. Phosphorylation of the Drosophila adherens junction protein Armadillo: roles for wingless signal and zeste-white 3 kinase.
    Dev Biol. 1994 Dec;166(2):543-56 PMID: 7529201
  44. The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding.
    Mol Cell Biol. 1995 Feb;15(2):614-25 PMID: 7823930
  45. Expression cloning of oncogenes by retroviral transfer of cDNA libraries.
    Mol Cell Biol. 1995 Feb;15(2):704-10 PMID: 7823939
  46. Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells.
    J Biol Chem. 1995 Jan 20;270(3):987-90 PMID: 7836418
  47. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site.
    Oncogene. 1997 Jun 5;14(22):2619-31 PMID: 9178760
  48. beta-catenin is a target for the ubiquitin-proteasome pathway.
    EMBO J. 1997 Jul 1;16(13):3797-804 PMID: 9233789
  49. Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts.
    Mol Cell Biol. 1997 Aug;17(8):4442-53 PMID: 9234702
  50. GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl.
    J Biol Chem. 1997 Sep 12;272(37):23285-91 PMID: 9287338
  51. GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells.
    J Biol Chem. 1998 Mar 20;273(12):7123-6 PMID: 9507025
  52. Beta-catenin: a key mediator of Wnt signaling.
    Curr Opin Genet Dev. 1998 Feb;8(1):95-102 PMID: 9529612
  53. The Yin-Yang of TCF/beta-catenin signaling.
    Adv Cancer Res. 2000;77:1-24 PMID: 10549354
  54. Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity.
    Mol Cell Biol. 1999 Dec;19(12):8075-82 PMID: 10567533
  55. beta-catenin signaling and cancer.
    Bioessays. 1999 Dec;21(12):1021-30 PMID: 10580987
  56. Cellular survival: a play in three Akts.
    Genes Dev. 1999 Nov 15;13(22):2905-27 PMID: 10579998
  57. Cell proliferation and apoptosis.
    Curr Opin Cell Biol. 1999 Dec;11(6):745-52 PMID: 10600713
  58. Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway.
    Blood. 2000 Jan 15;95(2):633-8 PMID: 10627473
  59. Regulation of beta-catenin signaling in the Wnt pathway.
    Biochem Biophys Res Commun. 2000 Feb 16;268(2):243-8 PMID: 10679188
  60. The control of beta-catenin and TCF during embryonic development and cancer.
    Cancer Metastasis Rev. 1999;18(2):231-46 PMID: 10728986
  61. Glycogen synthase kinase-2 and phosphorylase kinase are the same enzyme.
    Eur J Biochem. 1979 Oct 15;100(2):339-47 PMID: 41708
  62. Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, and extension of the N-terminal sequence containing the site phosphorylated by phosphorylase kinase.
    Eur J Biochem. 1980 Jun;107(2):529-37 PMID: 6772446
  63. PDGF induction of tyrosine phosphorylation of GTPase activating protein.
    Nature. 1989 Dec 7;342(6250):711-4 PMID: 2480526
  64. Receptor tyrosine kinases expressed in metastatic colon cancer.
    Int J Cancer. 1995 Mar 16;60(6):791-7 PMID: 7896447
  65. Mouse mammary tumors express elevated levels of RNA encoding the murine homology of SKY, a putative receptor tyrosine kinase.
    J Biol Chem. 1995 Mar 24;270(12):6872-80 PMID: 7896835
  66. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.
    FEBS Lett. 1995 May 8;364(2):229-33 PMID: 7750577
  67. Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3.
    Cell. 1995 Aug 11;82(3):355-8 PMID: 7634325
  68. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.
    Nature. 1995 Aug 17;376(6541):599-602 PMID: 7637810
  69. Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase.
    Trends Biochem Sci. 1995 Aug;20(8):303-7 PMID: 7667888
  70. The tumor promoter receptor protein kinase C: a novel target for chemoprevention and therapy of human colon cancer.
    Prog Clin Biol Res. 1995;391:117-20 PMID: 8532710
  71. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.
    J Biol Chem. 1995 Nov 17;270(46):27489-94 PMID: 7499206
  72. Signal transduction of beta-catenin.
    Curr Opin Cell Biol. 1995 Oct;7(5):634-40 PMID: 8573337
  73. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
    Nature. 1995 Dec 21-28;378(6559):785-9 PMID: 8524413
  74. Translational control of p27Kip1 accumulation during the cell cycle.
    Science. 1996 Mar 29;271(5257):1861-4 PMID: 8596954
  75. Identification of Gas6 as a growth factor for human Schwann cells.
    J Neurosci. 1996 Mar 15;16(6):2012-9 PMID: 8604045
  76. Cell adhesion: the molecular basis of tissue architecture and morphogenesis.
    Cell. 1996 Feb 9;84(3):345-57 PMID: 8608588
  77. Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl.
    J Biol Chem. 1996 Apr 19;271(16):9785-9 PMID: 8621659
  78. Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts.
    Oncogene. 1996 Feb 1;12(3):471-80 PMID: 8637702
  79. Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, gas6.
    FEBS Lett. 1996 May 27;387(1):78-80 PMID: 8654572
  80. Functional interaction of beta-catenin with the transcription factor LEF-1.
    Nature. 1996 Aug 15;382(6592):638-42 PMID: 8757136
  81. Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C.
    EMBO J. 1996 Sep 2;15(17):4526-36 PMID: 8887544
  82. PI3K: downstream AKTion blocks apoptosis.
    Cell. 1997 Feb 21;88(4):435-7 PMID: 9038334
  83. Wnt-1 induces growth, cytosolic beta-catenin, and Tcf/Lef transcriptional activation in Rat-1 fibroblasts.
    Mol Cell Biol. 1998 May;18(5):2474-85 PMID: 9566868
  84. The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells.
    J Biol Chem. 1998 Jun 5;273(23):14063-6 PMID: 9603900
  85. In vitro inhibition of Ras-Raf association by short peptides.
    Biochem Biophys Res Commun. 1998 Jun 9;247(1):176-80 PMID: 9636675
  86. WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells.
    Biochem Biophys Res Commun. 1998 Jun 29;247(3):851-8 PMID: 9647782
  87. Determinants for transformation induced by the Axl receptor tyrosine kinase.
    Oncogene. 1998 Jun 18;16(24):3177-87 PMID: 9671397
  88. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  89. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level.
    Genes Cells. 1998 Jun;3(6):395-403 PMID: 9734785
  90. Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer.
    Curr Opin Cell Biol. 1998 Oct;10(5):629-39 PMID: 9818174
  91. Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt.
    Mol Endocrinol. 1999 Feb;13(2):191-201 PMID: 9973250
  92. The oncogenic activation of beta-catenin.
    Curr Opin Genet Dev. 1999 Feb;9(1):15-21 PMID: 10072352
  93. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis.
    Nature. 1999 Apr 22;398(6729):723-8 PMID: 10227296
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.3.902-915.2001
Published
2001-02-00
Pages
902-15
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC86681
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.21.3.902-915.2001 PMC Full Text View journal details
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