In<i>Drosophila</i>, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1–Rok–Myosin-II and JNK signalling

Khoo, Peytee; Allan, Kirsten; Willoughby, Lee; Brumby, Anthony M.; Richardson, Helena E.

doi:10.1242/dmm.010066

Cited by 31 publications

(47 citation statements)

References 112 publications

(167 reference statements)

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“…Alternatively, JNK might be activated by other mechanisms independently of Eiger, or both processes might be operating together during disc regeneration. The JNK signalling pathway can be triggered via a number of means in different contexts [32–33], therefore we first examined the activity of JNK signalling in eiger 3 /eiger 1 regenerating discs. To this end we used a LacZ insertion in the gene puckered (puc) .…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Function of Apoptosis during Imaginal Wing Disc Regeneration in Drosophila melanogaster

2016

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Regeneration is the ability that allows organisms to replace missing organs or lost tissue after injuries. This ability requires the coordinated activity of different cellular processes, including programmed cell death. Apoptosis plays a key role as a source of signals necessary for regeneration in different organisms. The imaginal discs of Drosophila melanogaster provide a particularly well-characterised model system for studying the cellular and molecular mechanisms underlying regeneration. Although it has been shown that signals produced by apoptotic cells are needed for homeostasis and regeneration of some tissues of this organism, such as the adult midgut, the contribution of apoptosis to disc regeneration remains unclear. Using a new method for studying disc regeneration in physiological conditions, we have defined the pattern of cell death in regenerating discs. Our data indicate that during disc regeneration, cell death increases first at the wound edge, but as regeneration progresses dead cells can be observed in regions far away from the site of damage. This result indicates that apoptotic signals initiated in the wound spread throughout the disc. We also present results which suggest that the partial inhibition of apoptosis does not have a major effect on disc regeneration. Finally, our results suggest that during disc regeneration distinct apoptotic signals might be acting simultaneously.

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Section: Resultsmentioning

confidence: 99%

Analysis of the Function of Apoptosis during Imaginal Wing Disc Regeneration in Drosophila melanogaster

2016

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“…The cell death observed upon the complete loss of p120 in intestinal cells that also lack the tumor suppressor APC is effectively blocked by inhibition of Rho kinase, suggesting that Rho1 signaling is required for apoptosis [Short et al, 2017]. In Drosophila, the RhoGEF2-Rho1-Rho kinase-Myosin II pathway was linked to JNK activation [Neisch et al, 2010;Khoo et al, 2013], raising the possibility that loss of α-Cat may precipitate JNK activation through Rho1.…”

Section: Discussionmentioning

confidence: 99%

Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth

Sarpal

Yan

Kazakova

et al. 2019

Preprint

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α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling, to AJs but also through a mechanism that does not involve junctional recruitment of Ajuba. Further, both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat actin-binding domain affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

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“…In this regulatory pathway, RhoGEF2 successively activates Rho1, Rok (Rho kinase) and myosin II after cooperating with Ras ACT or Raf . Rok and myosin II then promote JNK (Jun kinase) activation together with Ras ACT [166]. JNK can inhibit cell differentiation and tissue growth and promote cell invasion.…”

Section: Myosin-mediated Factors Pathways and Models During Tumorigementioning

confidence: 99%

Myosins as fundamental components during tumorigenesis: diverse and indispensable

Yang

2016

Oncotarget

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Myosin is a kind of actin-based motor protein. As the crucial functions of myosin during tumorigenesis have become increasingly apparent, the profile of myosin in the field of cancer research has also been growing. Eighteen distinct classes of myosins have been discovered in the past twenty years and constitute a diverse superfamily. Various myosins share similar structures. They all convert energy from ATP hydrolysis to exert mechanical stress upon interactions with microfilaments. Ongoing research is increasingly suggesting that at least seven kinds of myosins participate in the formation and development of cancer. Myosins play essential roles in cytokinesis failure, chromosomal and centrosomal amplification, multipolar spindle formation and DNA microsatellite instability. These are all prerequisites of tumor formation. Subsequently, myosins activate various processes of tumor invasion and metastasis development including cell migration, adhesion, protrusion formation, loss of cell polarity and suppression of apoptosis. In this review, we summarize the current understanding of the roles of myosins during tumorigenesis and discuss the factors and mechanisms which may regulate myosins in tumor progression. Furthermore, we put forward a completely new concept of “chromomyosin” to demonstrate the pivotal functions of myosins during karyokinesis and how this acts to optimize the functions of the members of the myosin superfamily.

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InDrosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1–Rok–Myosin-II and JNK signalling

Cited by 31 publications

References 112 publications

Analysis of the Function of Apoptosis during Imaginal Wing Disc Regeneration in Drosophila melanogaster

Analysis of the Function of Apoptosis during Imaginal Wing Disc Regeneration in Drosophila melanogaster

Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth

Myosins as fundamental components during tumorigenesis: diverse and indispensable

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