The Nonmuscle Myosin Phosphatase PP1β (<i>flapwing</i>) Negatively Regulates Jun N-Terminal Kinase in Wing Imaginal Discs of Drosophila

Kirchner, Jasmin; Gross, Sascha; Bennett, Daimark; Alphey, Luke

doi:10.1534/genetics.106.067488

Cited by 14 publications

(18 citation statements)

References 48 publications

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“…Expression of the constitutively active Sqh EE (Jordan and Karess, 1997; Kirchner et al, 2007), is sufficient for apical constriction and invagination in the wing imaginal epithelium (Fig. 7C–C”, D), but the clones are not round like APC null clones (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with a role for active MyoII in APC null apical constriction, the doubly phosphorylated form of Sqh, but not total Sqh or singly phosphorylated Sqh, was enriched in apically constricting APC null cells (Zimmerman and McCartney, unpublished observations). Expression of a mutant form of Sqh in which both Ser-21 and Thr-20 have been replaced by alanines (Sqh AA ) (Jordan and Karess, 1997; Kirchner et al, 2007) in APC null cells suppressed apical constriction (Fig. 7F, G, H).…”

Section: Resultsmentioning

confidence: 99%

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Apical constriction and invagination downstream of the canonical Wnt signaling pathway require Rho1 and Myosin II

Zimmerman

Thorpe

Medrano

et al. 2010

Developmental Biology

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The tumor suppressor Adenomatous polyposis coli (APC) is a negative regulator of Wnt signaling and functions in cytoskeletal organization. Disruption of human APC in colonic epithelia initiates benign polyps that progress to carcinoma following additional mutations. The early events of polyposis are poorly understood, as is the role of canonical Wnt signaling in normal epithelial architecture and morphogenesis. To determine the consequences of complete loss of APC in a model epithelium, we generated APC2 APC1 double null clones in the Drosophila wing imaginal disc. APC loss leads to segregation, apical constriction, and invagination that result from transcriptional activation of canonical Wnt signaling. Further, we show that Wnt-dependent changes in cell fate can be decoupled from Wnt-dependent changes in cell shape. Wnt activation is reported to upregulate DE-cadherin in wing discs, and elevated DE-cadherin is thought to promote apical constriction. We find that apical constriction and invagination of APC null tissue are independent of DE-cadherin elevation, but are dependent on Myosin II activity. Further, we show that disruption of Rho1 suppresses apical constriction and invagination in APC null cells. Our data suggest a novel link between canonical Wnt signaling and epithelial structure that requires activation of the Rho1 pathway and Myosin II.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Apical constriction and invagination downstream of the canonical Wnt signaling pathway require Rho1 and Myosin II

Zimmerman

Thorpe

Medrano

et al. 2010

Developmental Biology

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“…Another study revealed that overexpression of wild-type Rho1 in the anterior-posterior boundary of the developing wing epithelium resulted in JNK-mediated apoptosis (Vidal et al, 2006). Myosin II activity has also been linked to JNK activation in a study of the Drosophila non-muscle myosin phosphatase PP1β (Flapwing), which negatively regulates JNK activity through the inhibition of Myosin II activity in the developing wing (Kirchner et al, 2007). Furthermore, a recent study has shown that depletion of the Sds22/PP1 phosphatase can cooperate with Ras ACT , via upregulation of Myosin II activity and JNK activation (Jiang et al, 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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“…The fact that not all sds22 deficient cells induce active JNK indicates that sds22/PP1 may regulate JNK activity indirectly through regulation of upstream components. Genetic studies suggest that Drosophila PP1β can regulate JNK through myosin II (Kirchner et al , 2007b). However, blocking myosin II activity in our study does not abolish the sds22/PP1 -mediated JNK activation (data not shown).…”

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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The Nonmuscle Myosin Phosphatase PP1β (flapwing) Negatively Regulates Jun N-Terminal Kinase in Wing Imaginal Discs of Drosophila

Cited by 14 publications

References 48 publications

Apical constriction and invagination downstream of the canonical Wnt signaling pathway require Rho1 and Myosin II

Apical constriction and invagination downstream of the canonical Wnt signaling pathway require Rho1 and Myosin II

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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