title: Oncogenic Shp2 disturbs microtubule regulation to cause HDAC6-dependent ERK hyperactivation.
abstract: Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyperactivation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. Here, we show that inhibition of RhoA-Dia is sufficient to upregulate ERK activation in epithelial cells. Oncogenic Shp2 expression attenuates RhoA-Dia signaling, by which microtubule (MT) is destabilized with reduced level of acetylation. Either MT stabilization, silencing of histone deacetylase 6 (HDAC6) or enforcing RhoA-Dia signal prevents oncogenic Shp2-induced ERK hyperactivation. We provide evidence that downregulation of RhoA-Dia-EB1 pathway by oncogenic Shp2 leads to HDAC6-mediated reduction in MT acetylation, in turn affecting ERK regulation. In response to serum stimulation, cells expressing wild-type Shp2 display transient ERK activation. In contrast, cells expressing oncogenic Shp2 have prolonged ERK activation. HDAC6 inhibition diminishes sustained activation of ERK and slows down the growth of these cells. Likewise, in human cancer cells, blocking Shp2 increases MT acetylation and decreases ERK phosphorylation, which are reversed by inhibition of Dia. As such, HDAC6 inhibition in these cells also reduces ERK activity. Our findings link MT regulation by HDAC6 to oncogenic Shp2 and ERK regulation, implicating the therapeutic potential of HDAC6 inhibitor in diseases involving Shp2 deregulation.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: S-C
authors.initials: SC
authors.lastname: Tien
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC [2] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020868:Gene Silencing; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020742:rhoA GTP-Binding Protein