Pleiotrophin disrupts calcium-dependent homophilic cell-cell adhesion and initiates an epithelial-mesenchymal transition
Pleiotrophin disrupts calcium-dependent homophilic cell-cell adhesion and initiates an epithelial-mesenchymal transition
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DOI：
10.1073/pnas.0607299103
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发表时间：
2006-11-21
影响因子：
11.1
通讯作者：
Deuel, T. F.
中科院分区：
文献类型：
--
作者：
Perez-Pinera, P.;Alcantara, S.;Deuel, T. F.
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)beta/xi 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 RPTP beta/xi: PTN inactivates RIPTP beta/xi, leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTP beta/xi at sites dephosphorylated by RPTP beta/xi in cells not stimulated by PTN. Thus, through the regulation of the tyrosine phosphatase activity of RPTP beta/xi the PTN/RIPTP beta/xi 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 RPTP beta/xi 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.
