title: In Drosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1-Rok-Myosin-II and JNK signalling.
abstract: The Ras oncogene contributes to ≈ 30% of human cancers, but alone is not sufficient for tumorigenesis. In a Drosophila screen for oncogenes that cooperate with an activated allele of Ras (Ras(ACT)) to promote tissue overgrowth and invasion, we identified the GTP exchange factor RhoGEF2, an activator of Rho-family signalling. Here, we show that RhoGEF2 also cooperates with an activated allele of a downstream effector of Ras, Raf (Raf(GOF)). We dissect the downstream pathways through which RhoGEF2 cooperates with Ras(ACT) (and Raf(GOF)), and show that RhoGEF2 requires Rho1, but not Rac, for tumorigenesis. Furthermore, of the Rho1 effectors, we show that RhoGEF2 + Ras (Raf)-mediated tumorigenesis requires the Rho kinase (Rok)-Myosin-II pathway, but not Diaphanous, Lim kinase or protein kinase N. The Rho1-Rok-Myosin-II pathway leads to the activation of Jun kinase (JNK), in cooperation with Ras(ACT). Moreover, we show that activation of Rok or Myosin II, using constitutively active transgenes, is sufficient for cooperative tumorigenesis with Ras(ACT), and together with Ras(ACT) leads to strong activation of JNK. Our results show that Rok-Myosin-II activity is necessary and sufficient for Ras-mediated tumorigenesis. Our observation that activation of Myosin II, which regulates Filamentous actin (F-actin) contractility without affecting F-actin levels, cooperates with Ras(ACT) to promote JNK activation and tumorigenesis, suggests that increased cell contractility is a key factor in tumorigenesis. Furthermore, we show that signalling via the Tumour necrosis factor (TNF; also known as Egr)-ligand-JNK pathway is most likely the predominant pathway that activates JNK upon Rok activation. Overall, our analysis highlights the need for further analysis of the Rok-Myosin-II pathway in cooperation with Ras in human cancers.
authors: Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
authors: Peytee
authors: P
authors: Khoo
authors: Kirsten
authors: K
authors: Allan
authors: Lee
authors: L
authors: Willoughby
authors: Anthony M
authors: AM
authors: Brumby
authors: Helena E
authors: HE
authors: Richardson
mesh_terms: D000818:Animals; D017209:Apoptosis; D057506:Arthropod Antennae / Q000254:growth & development; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002999:Clone Cells; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D024462:Myosin Type II / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011679:Pupa / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C090146:Rac1 protein, Drosophila; C465504:sav protein, Drosophila; D019908:Proto-Oncogene Proteins c-raf; C420924:Raf protein, Drosophila; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D024462:Myosin Type II; C511153:Rho1 protein, Drosophila; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins