Activation of JNK signaling links lgl mutations to disruption of the cell polarity and epithelial organization in Drosophila imaginal discs

Zhu, Mingwei; Xin, Tianchi; Weng, Shunyan; Gao, Yin; Zhang, Yingjie; Li, Qi; Li, Mingfa

doi:10.1038/cr.2010.2

Cited by 33 publications

(32 citation statements)

References 10 publications

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“…63 Whether these differences relate to the different tissue types or clonal versus homozygous tissues remains to be elucidated. The potential effects that blocking JNK has on the differentiation of lgl mutant tissue is also in contrast to that observed with blocking JNK in scrib -+ Ras V12 tumors, where it acts to restore invasive properties.…”

Section: Discussionmentioning

confidence: 99%

Lgl, the SWH pathway and tumorigenesis: It’s a matter of context and competition!

Grzeschik¹,

Parsons²,

Richardson³

2010

Cell Cycle

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Loss of function of the neoplastic tumors suppressors, lgl, scrib and dlg or overexpression of the apical polarity components, Crumbs and atypical protein kinase C (aPKC), are associated with polarity loss and tissue overgrowth, however, the mechanism behind these effects is poorly understood. In our recent study, we showed that Lgl, aPKC and Crumbs mediate their effects on proliferation and survival via the Salvador/Warts/Hippo (SWH) tumor suppressor pathway. Loss of lgl can lead to substantial overgrowth, however the lgl mutant phenotype can be quite variable and the amount of overgrowth of the mutant tissue, its survival and ultimate fate is strongly determined by context and competition. In this extra-view we present a more detailed description of the lgl mutant phenotype and highlight the phenotypic differences between lgl and SWH pathway mutant phenotypes. In addition, we explore the role for the Jun kinase (JNK) pathway in the development of the lgl mutant phenotype.

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Section: Discussionmentioning

confidence: 99%

Lgl, the SWH pathway and tumorigenesis: It’s a matter of context and competition!

Grzeschik¹,

Parsons²,

Richardson³

2010

Cell Cycle

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“…Although we have not yet tested the role of JNK in rok CAT or sqh EE cooperative tumorigenesis with Ras ACT , it most likely plays a similar role. Moreover, JNK might also contribute to cell morphology changes in Ras ACT -driven cooperative tumorigenesis, because blocking JNK activity in wing disc cells depleted for the apico-basal cell polarity regulator Lgl can rescue the cell morphology defects and rescue the overgrowth phenotype (Zhu et al, 2010). JNK might also contribute to the tumour overgrowth: a recent study showed that, in lgl- depleted wing disc tissue, JNK can inactivate the Hippo tissue growth control pathway, thereby promoting tissue overgrowth (Sun and Irvine, 2011).…”

Section: Discussionmentioning

confidence: 99%

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

Khoo

Allan

Willoughby

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYThe 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 (RasACT) 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 (RafGOF). We dissect the downstream pathways through which RhoGEF2 cooperates with RasACT (and RafGOF), 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 RasACT. Moreover, we show that activation of Rok or Myosin II, using constitutively active transgenes, is sufficient for cooperative tumorigenesis with RasACT, and together with RasACT 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 RasACT 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.

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“…However, blocking myosin II activity in our study does not abolish the sds22/PP1 -mediated JNK activation (data not shown). Alternatively, the JNK pathway can be activated by disruption of cell polarity genes (Brumby and Richardson, 2003; Ryoo et al , 2004; Zhu et al , 2010), suggesting that JNK could be a common downstream signal induced by the absence of these tumor suppressors. The role of cell polarity genes in mediating JNK activation downstream of sds22/PP1 will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling

et al. 2011

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Loss of epithelial integrity often correlates with the progression of malignant tumors. Sds22, a regulatory subunit of Protein Phosphatase 1 (PP1), has recently been linked to regulation of epithelial polarity in Drosophila. However, its role in tumorigenesis remains obscure. Here, using Drosophila imaginal tissue as an in vivo model system, we show that sds22 is a new potential tumor suppressor gene in Drosophila. Without sds22, cells lose epithelial architecture, and become invasive and tumorigenic when combined with Ras overexpression; conversely, sds22 overexpression can largely suppress tumorigenic growth of RasV12scrib−/ − mutant cells. Mechanistically, we show that sds22 prevents cell invasion and metastasis by inhibiting myosin II and JNK activity downstream of PP1. Loss of this inhibition causes cells to lose epithelial organization and promotes cell invasion. Finally, human Sds22 is focally deleted and down-regulated in multiple carcinomas, and this downregulation correlates with tumor progression, suggesting that sds22 inactivation may contribute to tumorigenesis and metastatic potential in human cancers via a similar mechanism.

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Activation of JNK signaling links lgl mutations to disruption of the cell polarity and epithelial organization in Drosophila imaginal discs

Cited by 33 publications

References 10 publications

Lgl, the SWH pathway and tumorigenesis: It’s a matter of context and competition!

Lgl, the SWH pathway and tumorigenesis: It’s a matter of context and competition!

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

Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling

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