Crumbs Regulates Salvador/Warts/Hippo Signaling in Drosophila via the FERM-Domain Protein Expanded

Robinson, Brian; Huang, Juang; Hong, Yang; Moberg, Kenneth H.

doi:10.1016/j.cub.2010.03.019

Cited by 287 publications

(357 citation statements)

References 52 publications

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“…Overexpression of full-length Crb or its intracellular domain was reported to drive tissue overgrowth characterized by loss of apical-basal polarity, elevated Yki activity and decreased Ex protein levels (27,28). Although these observations are suggestive of an oncogenic role for Crb, our current study using loss-offunction analysis clearly uncovers a tumor suppressor function for Crb.…”

Section: Discussionmentioning

confidence: 41%

“…This discrepancy may be due to distinct mutant-neighbor interactions encountered in the different studies. In the overexpression studies, Crb was expressed in whole compartments (27,28), whereas our study examined isolated clones-the latter situation, but not the former, allows interactions between cells with differential Crb activity. It is also possible that Crb overexpression causes a dominant-negative or neomorphic phenotype.…”

Section: Discussionmentioning

confidence: 99%

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The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

Chen

Zheng

Yin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.

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Section: Discussionmentioning

confidence: 41%

Section: Discussionmentioning

confidence: 99%

The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

Chen

Zheng

Yin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

293

352

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“…Since Moe is a negative regulator of Rho1 (Speck et al 2003), upregulation of Rib would be predicted to increase Rho1 activity to mediate its affects on cell morphology. Since Rib also upregulates crb transcription (Kerman et al 2008), and we and others have shown that high Crb levels deregulates the SWH signaling pathway to promote tissue growth Robinson et al 2010), it is possible that suppression of Rho1 activity in rib 1 Ras ACT eye discs unleashes this cryptic activity of Rib in tissue growth via its effect on Crb.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

et al. 2011

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We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (Ras ACT ) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with Ras ACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance Ras ACT -driven hyperplasia. Ras ACT -cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wildtype cells, only Rac1, an activated allele of Rho1 (Rho1 ACT ), RhoGEF2, and pbl cooperated with Ras ACT , resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with Ras ACT upregulated Jun kinase ( JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with Ras ACT , while in the clonal setting, JNK upregulation was sufficient for Ras ACT -mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of Ras V12 -expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2 1 human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with Ras ACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/ Rho-family/JNK pathway in cooperative tumorigenesis with Ras ACT .

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“…A number of cell polarity and cell adhesion proteins were also found to regulate the Hippo pathway. These include the Scribble (Scrib)-Discs large (Dlg)-Lethal giant larvae (Lgl) complex, atypical protein kinase C (aPKC), Crumbs (Crb) , and Echinoid (Ed) (Chen et al, 2010a;Grzeschik et al, 2010;Ling et al, 2010;Robinson et al, 2010;Yue et al, 2012), indicating a role of cell polarity and cell adhesion in Hippo pathway regulation. Furthermore, two studies identified Tao-1, a STE20 family protein kinase as a positive regulator of the Hippo pathway, possibly by directly phosphorylating and activating the Hpo kinase (Boggiano et al, 2011;Poon et al, 2011).…”

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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Crumbs Regulates Salvador/Warts/Hippo Signaling in Drosophila via the FERM-Domain Protein Expanded

Cited by 287 publications

References 52 publications

The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

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