Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

Li, Wei; Cooper, Jonathan M.; Zhou, Lü; Yang, Chenyi; Erdjument‐Bromage, Hediye; Zagzag, David; Snuderl, Matija; Ladanyi, Marc; Hanemann, C. Oliver; Zhou, Pengbo; Karajannis, Matthias A.; Giancotti, Filippo G.

doi:10.1016/j.ccr.2014.05.001

Cited by 190 publications

(208 citation statements)

References 43 publications

(71 reference statements)

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“…A WW domain-containing HECT class E3 ubiquitin ligase, ITCH, ubiquitinates LATS1 and promotes cell growth and survival (Ho et al 2011;Salah et al 2011). Another E3 ubiquitin ligase, CRL4 (DCAF1), which is activated in NF2-deficient tumor cells, inhibits LATS1 and LATS2 by ubiquitination in the nucleus (Li et al 2014b). Ubiquitination of LATS1/2 also plays a role in stress response and differentiation.…”

Section: Spatial Regulation Of Mst and Latsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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Section: Spatial Regulation Of Mst and Latsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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“…15,16 In Drosophila, Merlin cooperates with another FERM domain protein, Expanded, to accelerate endocytosis of specific receptors, including mitogenic receptors. 17 In addition, the role of Merlin in Hippo signaling, which is responsible for control of cell proliferation and organ size, has been intensively studied.…”

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confidence: 99%

Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation

Kim

et al. 2016

Cell Death Differ

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Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP 2 -dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease.

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“…Notably, LATS1 is cytoplasmic in luminal cells, which may prevent it from facilitating ERα degradation. Britschgi et al [5] speculate that cytosolic LATS can suppress YAP/ TAZ activity in luminal cells, although previous findings have indicated that LATS1/2 are predominantly active in the nucleus [7]. Further work is needed to fully understand in which subcellular compartment LATS1/2 are activated and target YAP in mammary stem cells and their progeny.…”

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confidence: 99%

“…In addition to restraining YAP activation, which drives stem cell self-renewal, LATS1/2 facilitate ERα ubiquitylation by the E3 ligase CRL4 DCAF1 , thereby suppressing luminal progenitor specification and differentiation. Adding to this complexity, NF2/Merlin suppresses the ability of CRL4 DCAF1 to target LATS, providing a mechanism for activation of YAP in NF2-mutant tumors [6,7].…”

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confidence: 99%

“…Consistently, LATS1 overexpression decreases and conversely, DCAF1 depletion increases ERα levels in cell lines. In light of prior evidence indicating that Merlin suppresses the ability of CRL4 DCAF1 to ubiquitylate LATS1 and target it for degradation [7], it is tempting to speculate that inactivation of Merlin, which occurs in a small fraction of breast cancers [12], may lead to activation of YAP and stabilization of ERα. On the other hand, CRL4 DCAF1 -mediated mono-and oligoubiquitylation of LATS2 inhibits kinase activity in lieu of degradation.…”

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confidence: 99%

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