The FERM-Domain Protein Expanded Regulates Hippo Pathway Activity via Direct Interactions with the Transcriptional Activator Yorkie

Badouel, Caroline; Gardano, Laura; Amin, Nancy; Garg, Ankush; Rosenfeld, Robyn; Bihan, Thierry Le; McNeill, Helen

doi:10.1016/j.devcel.2009.01.010

Cited by 189 publications

(206 citation statements)

References 42 publications

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“…S2 A and C). Ex has been shown to inhibit Yki independent of Wts by sequestering it at the plasma membrane (82,83). However, we did not observe changes of Kib protein levels in ex e1 mutant clones in the brain (Fig.…”

Section: Significancementioning

confidence: 53%

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

Gailite

Aerne

Tapon

2015

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

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The Hippo (Hpo) pathway is a highly conserved tumor suppressor network that restricts developmental tissue growth and regulates stem cell proliferation and differentiation. At the heart of the Hpo pathway is the progrowth transcriptional coactivator Yorkie [Yki–Yes-activated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in mammals]. Yki activity is restricted through phosphorylation by the Hpo/Warts core kinase cascade, but increasing evidence indicates that core kinase-independent modes of regulation also play an important role. Here, we examine Yki regulation in the Drosophila larval central nervous system and uncover a Hpo/Warts-independent function for the tumor suppressor kinase liver kinase B1 (LKB1) and its downstream effector, the energy sensor AMP-activated protein kinase (AMPK), in repressing Yki activity in the central brain/ventral nerve cord. Although the Hpo/Warts core cascade restrains Yki in the optic lobe, it is dispensable for Yki target gene repression in the late larval central brain/ventral nerve cord. Thus, we demonstrate a dramatically different wiring of Hpo signaling in neighboring cell populations of distinct developmental origins in the central nervous system.

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Section: Significancementioning

confidence: 53%

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

Gailite

Aerne

Tapon

2015

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

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“…In overexpression studies in cultured cells, Wts, Ex and Hpo can interact with Yki and repress its activity in a phosphorylation-independent mechanism. 31,32 We found that Wbp2 depletion reduced overgrowth of tissues harbouring amorphic alleles of wts, showing that Wbp2 exerts an effect epistatically to Wts. Therefore, Wbp2 does not activate Yki by interfering with Wts-mediated Yki repression, whether it is dependent or independent of phosphorylation.…”

Section: Discussionmentioning

confidence: 89%

Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador–Warts–Hippo pathway

et al. 2011

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The Salvador-Warts-Hippo (SWH) pathway is a key controller of tissue growth in both flies and mammals, and deregulation of pathway activity contributes to tumour formation. The SWH pathway regulates cell growth, proliferation and apoptosis by restricting activity of the Yorkie transcriptional co-activator protein. The proteins that function together with Yorkie to drive transcription and tissue growth are beginning to be revealed and include the Scalloped (Sd), Teashirt (Tsh) and Homothorax (Hth) transcription factors. In this study, we define Wbp2 as a promoter of Yorkie-dependent growth of Drosophila melanogaster tissues. Mammalian WBP2 was previously identified as a protein that interacts with the mammalian Yorkie homologue, Yes-associated protein. WBP2 has been shown to enhance steroid hormone-dependent transcription in cultured cells but its in vivo function has remained obscure. We show that D. melanogaster Wbp2 interacts with Yorkie in a WW domain-and PY motif-dependent manner and that Wbp2 can enhance Yorkie's transcriptional co-activator properties. In vivo, Wbp2 is required for growth of the D. melanogaster wing, and reduction of Wbp2 expression suppresses overgrowth of tissues that lack the warts growth-suppressive gene. Collectively, these studies define an important role for Wbp2 as a downstream component of the SWH tissue growth-control pathway.

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“…The nuclear accumulation of Yorkie is consistent with a loss of function in these experiments. Yorkie is the substrate of the Hippo signaling pathway regulated by Merlin and Expanded (12,(21)(22)(23). Therefore, restriction of motor-driven transport of an otherwise normal WT Merlin protein by an NF2 mutant protein results in the loss of function.…”

Section: Discussionmentioning

confidence: 99%

“…In Drosophila, mutation of a single threonine residue (T616) changes its distribution and association with various ligands, such as Moesin, another member of the ERM family (20). Both in vivo and in cultured cells, Merlin together with Expanded, have been shown to regulate cell growth and differentiation by promoting phosphorylation and cytoplasmic retention of the transcriptional coactivator Yorkie/YAP1 (12,(21)(22)(23). Moreover, recent studies suggest that through localization at the cortical actin network, Merlin controls the internalization and signaling of certain membrane receptors, including the epidermal growth factor (6, 9, 24-27).…”

mentioning

confidence: 99%

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

Benseñor

Barlan²,

Rice

et al. 2010

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

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The neurofibromatosis type 2 (NF2) tumor-suppressor protein Merlin is a member of the ERM family of proteins that links the cytoskeleton to the plasma membrane. In humans, mutations in the NF2 gene cause neurofibromatosis type-2 (NF2), a cancer syndrome characterized by the development of tumors of the nervous system. Previous reports have suggested that the subcellular distribution of Merlin is critical to its function, and that several NF2 mutants that lack tumor-suppressor activity present improper localization. Here we used a Drosophila cell culture model to study the distribution and mechanism of intracellular transport of Merlin and its mutants. We found that Drosophila Merlin formed cytoplasmic particles that move bidirectionally along microtubules. A single NF2-causing amino acid substitution in the FERM domain dramatically inhibited Merlin particle movement. Surprisingly, the presence of this immotile Merlin mutant also inhibited trafficking of the WT protein. Analysis of the movement of WT protein using RNAi and pull-downs showed that Merlin particles are associated with and moved by microtubule motors (kinesin-1 and cytoplasmic dynein), and that binding of motors and movement is regulated by Merlin phosphorylation. Inhibition of Merlin transport by expression of the dominant-negative mutant or depletion of kinesin-1 results in increased nuclear accumulation of the transcriptional coactivator Yorkie. These results demonstrate the requirement of microtubule-dependent transport for Merlin function.M erlin is a tumor-suppressor protein of the ERM family encoded by the NF2 gene that controls cell growth and contact-dependent inhibition of proliferation. Mutations in the NF2 gene are the underlying cause of neurofibromatosis type 2 (NF2), a familial cancer syndrome characterized by the development of sporadic tumors of the nervous system (1-3). To gain insight into Merlin's cellular functions, we have studied a Drosophila Merlin homolog and its disease-causing mutant. Drosophila Merlin shares the same fundamental domain composition as its mammalian counterpart, and several groups have obtained comparable results using the mammalian and Drosophila proteins (4).Merlin functions by organizing membrane domains that connect signals coming from the extracellular environment to cytoplasmic factors to ultimately regulate cellular proliferation (5-7). Consistent with this role, Merlin is concentrated in actin-rich structures, such as membrane ruffles in isolated cells and at cell-cell contacts in dense cultures (8-10). Merlin also exhibits a punctate distribution that has been attributed to localization to intracellular vesicles (7,11,12). Merlin has a dynamic distribution in Drosophila S2 cells. Studies have shown that the protein is initially localized along the cell cortical region and is then internalized in the form of particles (12, 13).Merlin mislocalization is associated with abnormal tissue growth and proliferation (12, 13). Many NF2 mutations of Merlin are abnormally distributed in the cells and lack tumor...

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The FERM-Domain Protein Expanded Regulates Hippo Pathway Activity via Direct Interactions with the Transcriptional Activator Yorkie

Cited by 189 publications

References 42 publications

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador–Warts–Hippo pathway

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

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