ReviewBench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesis
Section snippets
Introduction: organization and functions of the cadherin/catenin complex
Tissue integrity in multicellular organisms is dependent upon proper adhesion between adjacent cells. In mammalian epithelial cells, cell–cell adhesion is mediated by protein complexes organized into distinct functional structures termed tight junction, adherens junction and desmosome. The tight junction forms a diffusion barrier between cells and the extracellular environment [1] and desmosomes resist mechanical stress across the epithelium and maintain tissue integrity [2]. While both of
The cadherin/catenin complex in cancer
As would be expected for proteins essential in establishing and maintaining tissue integrity, loss of the cadherin/catenin complex plays a prominent role in cancer. Since defects in cadherin expression were first associated with cancer a few years after its discovery, the role and regulation of E-cadherin in many human cancers has been widely studied. The basis for changes in cadherin expression in cancer may be due to somatic or germline mutations, epigenetic modifications, transcriptional
Molecular and functional characterization of α-catenin in normal and cancer states
Alpha-catenin was discovered in 1984 by Vestweber and Kemler as a 102 kDa protein associated with the adhesion molecule E-cadherin (originally termed uvomorulin) [29], [30]. Even before the identification of its amino acid sequence, the function of α-catenin as a linker between E-cadherin and the actin cytoskeleton had been proposed [31]; E-cadherin co-localized with actin bundles, was present in a Triton-X insoluble fraction and became soluble upon deletion of the catenin binding domain [31].
A new model of α-catenin as a local regulator of the actin cytoskeleton and membrane dynamics
Although data from human cancers indicate that α-catenin may have functions distinct from those directly associated with E-cadherin, cancer researchers could not explain these data based upon the well-accepted model of α-catenin as a direct link between the cadherin/catenin complex to the actin cytoskeleton. However, the first clues that α-catenin has additional molecular functions came from the conditional deletion of α-catenin in surface and oral epithelia in mouse embryos [53]. Consistent
Cytoplasmic accumulation of α-catenin
Although loss of α-catenin mRNA and protein in cancer cells can be attributed to epigenetic mechanisms of gene silencing, there are instances where loss of plasma membrane staining and subsequent cytoplasmic accumulation of α-catenin are associated with increased metastasis [59], [60] and decreased patient survival [47], [61], [62]. The new model of α-catenin function posits that α-catenin conformation in the cytoplasmic pool is key to α-catenin function, rather than the membrane associated
Alpha-catenin in cell proliferation
Loss of α-catenin expression often leads to increased cell proliferation. This has been observed in cancer cell lines [89] and after α-catenin deletion in mouse epidermis and central nervous system [53], [90]. As uncontrolled growth is a hallmark of human cancers, understanding the inhibitory effects of α-catenin on proliferation is critical. Although the mechanisms underlying this regulation are not understood, α-catenin is involved in multiple signaling pathways that regulate cell
Concluding remarks
Previously, α-catenin was considered to be a simple structural linker between the cadherin/catenin complex and the actin cytoskeleton. Recent studies, and a re-evaluation of cancer data in light of new models of α-catenin function, indicate that α-catenin is at the nexus of multiple pathways controlling actin and membrane dynamics, proliferation and apoptosis, and growth factor signaling.
In general, disruption of the cadherin/catenin complex is a prognostic factor for cancer progression, but in
Acknowledgements
We thank members of the Nelson lab for critical reading of the manuscript. J.M.B. is a student in the Cancer Biology Program and is supported by a Stanford Graduate Fellowship. Work from the Nelson laboratory was supported by the NIH (GM35527).
References (204)
- et al.
Tight junctions: molecular architecture and function
Int Rev Cytol
(2006) - et al.
Sticky business: orchestrating cellular signals at adherens junctions
Cell
(2003) - et al.
Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition
Curr Opin Cell Biol
(2005) The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover
J Biol Chem
(2001)- et al.
The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin
Curr Opin Cell Biol
(2005) - et al.
Regulation of Cell Adhesion by Protein-tyrosine Phosphatases: II. Cell–cell adhesion
J Biol Chem
(2006) - et al.
Molecular requirements for epithelial-mesenchymal transition during tumor progression
Curr Opin Cell Biol
(2005) - et al.
Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues
Exp Cell Res
(1984) - et al.
Some structural and functional aspects of the cell adhesion molecule uvomorulin
Cell Differ
(1984) Comprehensive genome-wide comparison of DNA and RNA level scan using microarray technology for identification of candidate cancer-related genes in the HL-60 cell line
Cancer Genet Cytogenet
(2003)
Marked allelic imbalance on chromosome 5q31 does not explain alpha-catenin expression in epithelial ovarian cancer
Gynecol Oncol
Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin
Cell
Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly
Cell
Deconstructing the cadherin-catenin-actin complex
Cell
Structure of the dimerization and beta-catenin-binding region of alpha-catenin
Mol Cell
Cellular motility driven by assembly and disassembly of actin filaments
Cell
Re-solving the cadherin-catenin-actin conundrum
J Biol Chem
The role of Shp2 (PTPN11) in cancer
Curr Opin Genet Dev
Proteomic analysis of in vivo phosphorylated synaptic proteins
J Biol Chem
IQGAP1 promotes cell motility and invasion
J Biol Chem
Overexpression and diffuse expression pattern of IQGAP1 at invasion fronts are independent prognostic parameters in ovarian carcinomas
Cancer Lett
Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts
Cancer Lett
Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma
Mod Pathol
Connexins as targets for cancer chemoprevention and chemotherapy
Biochim Biophys Acta
Impaired trafficking of connexins in androgen-independent human prostate cancer cell lines and its mitigation by alpha-catenin
J Biol Chem
The Ras/Raf/MAPK pathway
J Thorac Oncol
Dysregulation of E-cadherin by oncogenic Ras in intestinal epithelial cells is blocked by inhibiting MAP kinase
Am J Surg
E-cadherin is regulated by the transcriptional repressor SLUG during Ras-mediated transformation of intestinal epithelial cells
Surgery
Catenins: keeping cells from getting their signals crossed
Dev Cell
The desmosome: cell science lessons from human diseases
J Cell Sci
Identification of a putative cell adhesion domain of uvomorulin
EMBO J
E-cadherin null mutant embryos fail to form a trophectoderm epithelium
Proc Natl Acad Sci USA
An alpha-E-catenin gene trap mutation defines its function in preimplantation development
Proc Natl Acad Sci USA
Complex networks orchestrate epithelial-mesenchymal transitions
Nat Rev Mol Cell Biol
C-cadherin ectodomain structure and implications for cell adhesion mechanisms
Science
Proteolytic E-cadherin activation followed by solution NMR and X-ray crystallography
EMBO J
Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells
J Cell Biol
Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly
J Cell Biol
Assembly of the cadherin-catenin complex in vitro with recombinant proteins
J Cell Sci
Alpha 1 (E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex
Proc Natl Acad Sci USA
A core function for p120-catenin in cadherin turnover
J Cell Biol
p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction
Mol Cell Biol
Cadherin and catenin alterations in human cancer
Genes Chromosomes Cancer
Cell adhesion and signalling by cadherins and Ig-CAMs in cancer
Nat Rev Cancer
Dissemination and growth of cancer cells in metastatic sites
Nat Rev Cancer
Cancer staging: future directions for the TNM classification
Semin Surg Oncol
Grading and scoring in histopathology
Histopathology
Emerging roles for p120-catenin in cell adhesion and cancer
Oncogene
Convergence of Wnt, beta-catenin, and cadherin pathways
Science
Cited by (102)
Hereditary diffuse gastric cancer (HDGC). An overview
2022, Clinics and Research in Hepatology and GastroenterologyCell Polarity
2022, Encyclopedia of Cell Biology: Volume 1-6, Second EditionAnalysis of a vinculin homolog in a sponge (phylum Porifera) reveals that vertebrate-like cell adhesions emerged early in animal evolution
2018, Journal of Biological ChemistryCell- cell adhesion in metazoans relies on evolutionarily conserved features of The -catenin-catenin- binding interface
2017, Journal of Biological ChemistryFascin2 regulates cisplatin-induced apoptosis in NRK-52E cells
2017, Toxicology Letters