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A Cryptic Frizzled Module in Cell Surface Collagen 18 Inhibits Wnt/β−Catenin Signaling

By Delphine Quélard, Elise Lavergne, Ismaïl Hendaoui, Harri Elamaa, Ulla Tiirola, Ritva Heljasvaara, Taina Pihlajaniemi, Bruno Clément and Orlando Musso

Abstract

Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors. We show that V3C18 is a cell surface heparan sulfate proteoglycan, its topology being mediated by the FZC18 module. V3C18 mRNA was expressed at low levels in 21 normal adult human tissues. Its expression was up-regulated in fibrogenesis and in small well-differentiated liver tumors, but decreased in advanced human liver cancers. Low FZC18 immunostaining in liver cancer nodules correlated with markers of high Wnt/β−catenin activity. V3C18 (Mr = 170 kD) was proteolytically processed into a cell surface FZC18-containing 50 kD glycoprotein precursor that bound Wnt3a in vitro through FZC18 and suppressed Wnt3a-induced stabilization of β−catenin. Ectopic expression of either FZC18 (35 kD) or its 50 kD precursor inhibited Wnt/β−catenin signaling in colorectal and liver cancer cell lines, thus downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth. By contrast, full-length V3C18 was unable to inhibit Wnt signaling. In summary, we identified a cell-surface signaling pathway whereby FZC18 inhibits Wnt/β−catenin signaling. The signal, encrypted within cell-surface C18, is released by enzymatic processing as an active frizzled cysteine-rich domain (CRD) that reduces cancer cell growth. Thus, extracellular matrix controls Wnt signaling through a collagen-embedded CRD behaving as a cell-surface sensor of proteolysis, conveying feedback cues to control cancer cell fate

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2270346
Provided by: PubMed Central
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    Citations

    1. (1994). Alpha 1(XVIII), a collagen chain with frequent interruptions in the collagenous sequence, a distinct tissue distribution, and homology with type XV collagen.
    2. (2004). An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells.
    3. (2006). Apc tumor suppressor gene is the ‘‘zonation-keeper’’ of mouse liver.
    4. (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
    5. (2003). Betacatenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes.
    6. Blobel CP (2007) In search of partners: linking extracellular proteases to substrates.
    7. (2005). Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations.
    8. (1998). Cell cycle regulation and apoptosis.
    9. (2003). Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif.
    10. (1996). Characterization of the mouse gene for the alpha 1 chain of type XVIII collagen (Col18a1) reveals that the three variant N-terminal polypeptide forms are transcribed from two widely separated promoters.
    11. (1998). Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver.
    12. (1996). Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
    13. (2007). Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas.
    14. (1997). Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
    15. (2004). Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer.
    16. (1999). Exogenous expression of beta-catenin regulates contact inhibition, anchorage-independent growth, anoikis, and radiation-induced cell cycle arrest.
    17. (2005). Expression of Frzb/ secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness.
    18. (2006). Genetics of hepatocellular tumors.
    19. (2007). Helping Wingless take flight: how WNT proteins are secreted.
    20. (2006). Human bradykinin B2 receptor sialylation and N-glycosylation participate with disulfide bonding in surface receptor dimerization.
    21. (1998). Identification of c-MYC as a target of the APC pathway.
    22. (1995). Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins.
    23. (2002). Infection of a human hepatoma cell line by hepatitis B virus.
    24. (2004). Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells.
    25. (2001). Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.
    26. (2001). Interaction of endostatin with integrins implicated in angiogenesis.
    27. (1999). Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.
    28. (1995). Kahn A
    29. (2004). Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas.
    30. (2002). Matricellular proteins: extracellular modulators of cell function.
    31. (1983). Mitochondrial metabolism of glutamine and glutamate and its physiological significance.
    32. (1998). Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with betacatenin.
    33. (1995). Mouse Col18a1 is expressed in a tissue-specific manner as three alternative variants and is localized in basement membrane zones.
    34. (2002). Overexpression of glutamine synthetase is associated with beta-cateninmutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital.
    35. (2006). Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma.
    36. (1997). SARPs: a family of secreted apoptosis-related proteins.
    37. (1998). Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.
    38. (2003). Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector.
    39. (1998). Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin.
    40. (1967). Studies on plasma membranes. IV. The ultrastructural localization and content of sialic acid in plasma membranes isolated from rat liver and hepatoma.
    41. (1998). The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases.
    42. (2000). The promoter of the long variant of collagen XVIII, the precursor of endostatin, contains liverspecific regulatory elements.
    43. (1998). The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans.
    44. (2007). The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo.
    45. (2004). The Wnt antagonist sFRP1 in colorectal tumorigenesis.
    46. (1996). trans-Acting factors, detoxication enzymes and hepatitis B virus replication in a novel set of human hepatoma cell lines.
    47. (2001). Tumor hepatocytes and basement membrane producing cells specifically express two different forms of the endostatin precursor collagen XVIII in human liver cancers.
    48. (2001). Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas.
    49. (2002). Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis.
    50. (2001). Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription.
    51. (2006). Wnt/beta-catenin signaling in development and disease.
    52. (2006). Wnts as ligands: processing, secretion and reception.
    53. (2003). Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements.

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