Morgana/chp-1, a ROCK Inhibitor Involved in Centrosome Duplication and Tumorigenesis

• Published in: Developmental cell Vol. 18; no. 3; pp. 486 - 495
• Main Authors: Ferretti, Roberta, Palumbo, Valeria, Di Savino, Augusta, Velasco, Silvia, Sbroggiò, Mauro, Sportoletti, Paolo, Micale, Lucia, Turco, Emilia, Silengo, Lorenzo, Palumbo, Gioacchino, Hirsch, Emilio, Teruya-Feldstein, Julie, Bonaccorsi, Silvia, Pandolfi, Pier Paolo, Gatti, Maurizio, Tarone, Guido, Brancaccio, Mara
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 16-03-2010; Cell Press
• Subjects: Animals; Biological and medical sciences; Breast Neoplasms - genetics; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; CELLBIO; CELLCYCLE; Centrosome - metabolism; Centrosome - pathology; Down-Regulation; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Embryonic Development - genetics; Embryonic Development - physiology; Enzyme Inhibitors - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fungal Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Mice; Mice, Knockout; Mitosis - genetics; Mitosis - physiology; Molecular and cellular biology; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Mutation; Neoplasms, Experimental - etiology; Nuclear Proteins - metabolism; Pregnancy; rho-Associated Kinases - antagonists & inhibitors; SIGNALING; CELLBIO; CELLCYCLE; SIGNALING; Development; Inhibitor; Duplication; Carcinogenesis; Centrosome
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2009.12.020

Centrosome abnormalities lead to genomic instability and are a common feature of many cancer cells. Here we show that mutations in morgana/chp-1 result in centrosome amplification and lethality in both Drosophila and mouse, and that the fly centrosome phenotype is fully rescued by the human ortholog of morgana. In mouse cells, morgana forms a complex with Hsp90 and ROCK I and II, and directly binds ROCK II. Morgana downregulation promotes the interaction between ROCK II and nucleophosmin (NPM), leading to an increased ROCK II kinase activity, which results in centrosome amplification. morgana+/− primary cells and mice display an increased susceptibility to neoplastic transformation. In addition, tumor tissue array histochemical analysis revealed that morgana is underexpressed in a large fraction of breast and lung human cancers. Thus, morgana/chp-1 appears to prevent both centrosome amplification and tumorigenesis.
► morgana is an essential gene in both mouse and Drosophila ► Morgana underexpression enhances ROCK activity leading to centrosome amplification ► Morgana restrains ROCK kinase activity by countering NPM-dependent ROCK activation ► Morgana underexpression promotes transformation and occurs in many human cancers