Pleiotrophin disrupts calcium-dependent homophilic cell-cell adhesion and initiates an epithelial-mesenchymal transition

P. Perez-Pinera, S. Alcantara, T. Dimitrov, J. A. Vega, T. F. Deuel

Research output: Contribution to journalArticlepeer-review

Abstract

Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of proteins in different signaling pathways and other cellular systems, but how the steady-state levels of tyrosine phosphorylation are coordinated in different cellular systems to initiate complex cellular functions remains a formidable challenge. The receptor protein tyrosine phosphatase (RPTP)β/ζ is a transmembrane tyrosine phosphatase whose substrates include proteins important in intracellular and transmembrane protein-signaling pathways, cytoskeletal structure, cell-cell adhesion, endocytosis, and chromatin remodeling. Pleiotrophin (PTN the protein and Ptn the gene) is a ligand for RPTPβ/ζ; PTN inactivates RPTPβ/ζ, leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTPβ/ζ at sites dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN. Thus, through the regulation of the tyrosine phosphatase activity of RPTPβ/ζ, the PTN/RPTPβ/ζ signaling pathway coordinately regulates the levels of tyrosine phosphorylation of proteins in many cellular systems. We now demonstrate that PTN disrupts cytoskeletal protein complexes, ablates calcium-dependent homophilic cell-cell adhesion, stimulates ubiquitination and degradation of N-cadherin, reorganizes the actin cytoskeleton, and induces a morphological epithelial-mesenchymal transition (EMT) in PTN-stimulated U373 cells. The data suggest that increased tyrosine phosphorylation of the different substrates of RPTPβ/ζ in PTN-stimulated cells alone is sufficient to coordinately stimulate the different functions needed for an EMT; it is possible that PTN initiates an EMT in cells at sites where PTN is expressed in development and in malignant cells that inappropriately express Ptn.

Original languageEnglish (US)
Pages (from-to)17795-17800
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number47
DOIs
StatePublished - Nov 21 2006
Externally publishedYes

Keywords

  • β-catenin
  • Cadherin
  • Cytoskeleton
  • Glioblastoma
  • Receptor protein tyrosine phosphataseβ/ζ

ASJC Scopus subject areas

  • Genetics
  • General

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