Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant

• Published in: Oncogene Vol. 19; no. 1; pp. 75 - 84
• Main Authors: INAGAKI, K, NOGUCHI, T, MATOZAKI, T, HORIKAWA, T, FUKUNAGA, K, TSUDA, M, ICHIHASHI, M, KASUGA, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 06.01.2000; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Cell Adhesion; Cell adhesion & migration; Cell growth; Cell migration; Cell Movement; Cell physiology; Cellular signal transduction; CHO Cells; Cricetinae; Cytoskeletal Proteins - metabolism; Cytoskeleton - chemistry; Epidermal growth factor; Extracellular matrix; Fundamental and applied biological sciences. Psychology; Gene expression; Insulin; Insulin - pharmacology; Integrins - physiology; Intracellular Signaling Peptides and Proteins; Kinases; Ligands; Molecular and cellular biology; Paxillin; Phosphatase; Phosphatases; Phosphoproteins - metabolism; Phosphorylation; Physiological aspects; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - physiology; protein-tyrosine-phosphatase; Proteins; Rats; SHP2 protein; Signal transduction; Tyrosine - metabolism; Japan; Enzyme; Migration; Cell adhesion molecule; Phosphoric monoester hydrolases; Cell cell interaction; Esterases; Adhesion; Cell motility; Signal transduction; Vertebrata; Integrin; Cell line; Mammalia; Hydrolases; Cytoskeleton; Protein-tyrosine-phosphatase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203204

SHP-2, a SRC homology 2 domain-containing protein tyrosine phosphatase, mediates activation of Ras and mitogen-activated protein kinase by various mitogens and cell adhesion. Inhibition of endogenous SHP-2 by overexpression of a catalytically inactive (dominant negative) mutant in Chinese hamster ovary cells or Rat-1 fibroblasts has now been shown to induce a marked change in cell morphology (from elongated to less polarized) that is accompanied by substantial increases in the numbers of actin stress fibers and focal adhesion contacts. Overexpression of the SHP-2 mutant also increased the strength of cell-substratum adhesion and resulted in hyperphosphorylation of SHPS-1, a substrate of SHP-2 that contributes to cell adhesion-induced signaling. Inhibition of SHP-2 also markedly increased the rate of cell attachment to and cell spreading on extracellular matrix proteins such as fibronectin and vitronectin, effects that were accompanied by enhancement of adhesion-induced tyrosine phosphorylation of paxillin and p130Cas. In addition, cell migration mediated by fibronectin or vitronectin, but not that induced by insulin, was impaired by overexpression of the SHP-2 mutant. These results suggest that SHP-2 plays an important role in the control of cell shape by contributing to cytoskeletal organization, and that it is an important regulator of integrin-mediated cell adhesion, spreading, and migration as well as of tyrosine phosphorylation of focal adhesion contact-associated proteins.