title: The Shp2-induced epithelial disorganization defect is reversed by HDAC6 inhibition independent of Cdc42.
abstract: Regulation of Shp2, a tyrosine phosphatase, critically influences the development of various diseases. Its role in epithelial lumenogenesis is not clear. Here we show that oncogenic Shp2 dephosphorylates Tuba to decrease Cdc42 activation, leading to the abnormal multi-lumen formation of epithelial cells. HDAC6 suppression reverses oncogenic Shp2-induced multiple apical domains and spindle mis-orientation during division in cysts to acquire normal lumenogenesis. Intriguingly, Cdc42 activity is not restored in this rescued process. We present evidence that simultaneous reduction in myosin II and ERK1/2 activity by HDAC6 inhibition is responsible for the reversion. In HER2-positive breast cancer cells, Shp2 also mediates Cdc42 repression, and HDAC6 inhibition or co-suppression of ERK/myosin II promotes normal epithelial lumen phenotype without increasing Cdc42 activity. Our data suggest a mechanism of epithelial disorganization by Shp2 deregulation, and reveal the cellular context where HDAC6 suppression is capable of establishing normal epithelial lumenogenesis independent of Cdc42.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street,Taipei 11221, Taiwan.
authors.forename: Sui-Chih
authors.initials: SC
authors.lastname: Tien
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, No. 155, Section 2, Linong Street,Taipei 11221, Taiwan.
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street,Taipei 11221, Taiwan.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.
authors.forename: Miao-Hsia
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Section 2, Linong Street,Taipei 11221, Taiwan.
authors.forename: Zee-Fen
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D000818:Animals; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D020764:cdc42 GTP-Binding Protein