Location of Repository

Nuclear translocation and signalling of L1-CAM in human carcinoma cells requires ADAM10 and presenilin/gamma-secretase activity

By Svenja Riedle, Helena Kiefel, Daniela Gast, Sandra Bondong, Silke Wolterink, Paul Gutwein and Peter Altevogt

Abstract

L1-CAM (L1 cell-adhesion molecule), or more simply L1, plays an important role in the progression of human carcinoma. Overexpression promotes tumour-cell invasion and motility, growth in nude mice and tumour metastasis. It is feasible that L1-dependent signalling contributes to these effects. However, little is known about its mechanism in tumour cells. We reported previously that L1 is cleaved by ADAM (a disintegrin and metalloprotease) and that the cytoplasmic part is essential for L1 function. Here we analysed more closely the role of proteolytic cleavage in L1-mediated nuclear signalling. Using OVMz carcinoma cells and L1-transfected cells as a model, we found that ADAM10-mediated cleavage of L1 proceeds in lipid raft and non-raft domains. The cleavage product, L1-32, is further processed by PS (presenilin)/gamma-secretase to release L1-ICD, an L1 intracellular domain of 28 kDa. Overexpression of dominantnegative PS1 or use of a specific gamma-secretase inhibitor leads to an accumulation of L1-32. Fluorescence and biochemical analysis revealed a nuclear localization for L1-ICD. Moreover, inhibition of ADAM10 and/or gamma-secretase blocks nuclear translocation of L1-ICD and L1-dependent gene regulation. Overexpression of recombinant L1-ICD mediates gene regulation in a similar manner to full-length L1. Our results establish for the first time that regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines. Key words: a disintegrin and metalloprotease 10 (ADAM10), L1 cell-adhesion molecule (L1-CAM), nuclear translocation, presenilin (PS)/gamma-secretase activity, raft, signalling

Topics: ddc:610
Year: 2009
OAI identifier: oai:publikationen.ub.uni-frankfurt.de:7143

Suggested articles

Preview

Citations

  1. (2003). A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations.
  2. (2001). A portrait of Alzheimer secretases – new features and familiar faces.
  3. (1999). A PS-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain.
  4. (2002). A PS-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions.
  5. (2006). A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44.
  6. (2008). accepted 5
  7. (2003). ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles.
  8. (1998). Caveolae, plasma membrane microdomains for α-secretase-mediated processing of the amyloid precursor protein.
  9. (2003). Chronic activation of ERK and neurodegenerative diseases.
  10. (2005). Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells.
  11. (2001). Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts.
  12. (2006). Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signalling.
  13. (2003). Distinct endocytic pathways regulate TGF-β receptor signalling and turnover.
  14. (2001). Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins.
  15. (2002). Endolysosomal proteolysis and its regulation.
  16. (2007). Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis.
  17. (2004). Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion.
  18. (2004). Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signalling.
  19. (2003). Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic suppressor elements.
  20. (2002). Insulin-degrading enzyme rapidly removes the β-amyloid precursor protein intracellular domain (AICD).
  21. (1999). Integrin leukocyte function-associated antigen-1-mediated cell binding can be activated by clustering of membrane rafts.
  22. Kloppel, G.et al. (2007)Drug-inducedexpression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells.
  23. (2002). L1 endocytosis is controlled by a phosphorylation–dephosphorylation cycle stimulated by outside-in signalling by L1.
  24. (2002). L1 expressed by glioma cells promotes adhesion but not migration.
  25. (2007). L1 expression as a marker for poor prognosis, tumour progression, and short survival in patients with colorectal cancer.
  26. (2003). L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas.
  27. (2005). L1 is sequentially processed by two differently activated metalloproteases and PS/γ-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth.
  28. (2006). L1 on ovarian carcinoma cells is a binding partner for neuropilin-1 on mesothelial cells.
  29. (2007). L1-CAM in a membrane-bound or soluble form augments protection from apoptosis in ovarian carcinoma cells.
  30. (2005). L1, a novel target of β-catenin signalling, transforms cells and is expressed at the invasive front of colon cancers.
  31. (2000). Lipid rafts and signal transduction.
  32. (2002). Migration of nerve growth cones requires detergentresistant membranes in a spatially defined and substrate-dependent manner.
  33. (1999). Mitogen-activated protein kinases: specific messages from ubiquitous messengers.
  34. (1998). Molecular characterization of a novel, widespread nuclear protein that colocalizes with spliceosome components.
  35. (2006). MT1-MMP shedding involves an ADAM and is independent of its localization in lipid rafts.
  36. (1997). Neural recognition molecules and synaptic plasticity.
  37. (2002). Notch: a membrane-bound transcription factor.
  38. (2002). Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma.
  39. (1998). Palmitoylation of neurofascin at a site in the membrane-spanning domain highly conserved among the L1 family of cell adhesion molecules.
  40. (2001). Proteolytic release of CD44 intracellular domain and its role in the CD44 signalling pathway.
  41. (2002). PS-dependent γ-secretase-like intramembrane cleavage of ErbB4.
  42. (1991). rab5 controls early endosome fusion in vitro.C e l l64,
  43. (2000). Role of Src kinases in the ADAM-mediated release of L1 adhesion molecule from human tumour cells.
  44. (2005). Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein.
  45. Schneider,C.,Pantel,K.,Schachner,M.etal.(2007)L1isassociatedwithmicrometastatic spread and poor outcome in colorectal cancer.
  46. (2005). Shedding light on ADAM metalloproteinases.
  47. (2005). Spatial segregation of γ-secretase and substrates in distinct membrane domains.
  48. (2007). The cytoplasmic part of L1-CAM controls growth and gene expression in human tumours that is reversed by therapeutic antibodies.
  49. (2008). The differential role of L1 in ovarian carcinoma and normal ovarian surface epithelium.
  50. (1995). The F3 neuronal glycosylphosphatidylinositol-linked molecule is localized to glycolipid-enriched membrane subdomains and interacts with L1 and fyn kinase in cerebellum.
  51. (1998). The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via the clathrin-mediated pathway.
  52. (2008). The RGD integrin binding site in human L1-CAM is important for nuclear signalling.
  53. (2003). γ-Secretase activity is present in rafts but is not cholesteroldependent.
  54. (2001). γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.