Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway

Li, Youjun; Zhou, Hao; Li, Fengzhi; Chan, Siew Wee; Lin, Zhijie; Wei, Zhiyi; Zhou, Yang; Guo, Feng; Lim, Chun Jye; Xing, Wancai; Shen, Yuequan; Hong, Wanjin; Long, Jiafu; Zhang, Mingjie

doi:10.1038/cr.2015.69

Cited by 124 publications

(194 citation statements)

References 62 publications

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“…Although AMOT can induce LATS2-mediated phosphorylation of YAP and sequester YAP/TAZ to tight junctions (Chan et al, 2011; Paramasivam et al, 2011; Wang et al, 2011; Zhao et al, 2010a), AMOT is also reported to activate YAP by binding YAP in the cytoplasm to prevent LATS1/2-mediated phosphorylation and to promote transcription (Yi et al, 2013). Moreover, AMOT binds to and activates NF2 (Li et al, 2015). Here, in response to serum starvation, the AMOT KO cells were slightly more sensitive but overall did not show much difference from the wild-type cells.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Hippo Pathway Components by Gene Inactivation

et al. 2016

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SUMMARY The Hippo pathway is important for regulating tissue homeostasis and its dysregulation has been implicated in human cancer. However, it is not well understood how the Hippo pathway becomes dysregulated because few mutations in core Hippo pathway components have been identified. Therefore, much work in the Hippo field has focused on identifying upstream regulators, and a complex Hippo interactome has been identified. Nevertheless, it is not always clear which components are the most physiologically relevant in regulating YAP/TAZ. To provide an overview of important Hippo pathway components, we created knockout cell lines for many of these components and compared their relative contributions to YAP/TAZ regulation in response to a wide range of physiological signals. By this approach, we provide an overview of the functional importance of many Hippo pathway components and demonstrate NF2 and RHOA as important regulators of YAP/TAZ and TAOK1/3 as direct kinases for LATS1/2.

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Section: Resultsmentioning

confidence: 99%

Characterization of Hippo Pathway Components by Gene Inactivation

et al. 2016

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“…For example, we show in this study that USH1C binds to site 5 in F3 and site 6 formed by the F1/F2/F3 interface of Myo7b C-terminal FERM domain. In a number of FERM domain proteins with auto-inhibitory tails, each tail is known to simultaneously bind to sites 3 and 4 in the F3 and F2 lobes, respectively (31,47,48). The Crumbs tail is shown to simultaneous bind to site 1 in the F3-lobe and site 2 in the F1/F3 interface (49).…”

Section: Discussionmentioning

confidence: 99%

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

Weck

et al. 2017

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

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Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.M icrovilli and stereocilia are both actin bundle-based, fingerlike protrusions found on apical surfaces of many epithelial cells (1). Microvilli line the apical surface of epithelial cells forming a densely packed structure known as the brush border in tube-like tissues, such as intestines, kidney, and lung (2-5). The best known function of microvilli is to massively increase membrane surface area of these tissues to promote solute exchange, although these protrusions may also allow cells to communicate with their extracellular surroundings (6). Stereocilia, on the other hand, are composed of several rows of protrusions with graded height forming a staircase-like structure on the apical surface of inner ear hair cells, which collectively function to sense sound waves (7,8). Despite clear morphological and functional differences, microvilli and stereocilia share certain features at the molecular level. For example, the packing and organization of microvilli and stereocilia both rely on homologous cadherin-based tip-link complexes that target to the distal ends of these protrusions (9, 10). Additionally, a set of homologous unconventional myosins-including Myo1, Myo3, Myo6, and Myo7-are shared by and critical for the development, maintenance, and functions of microvilli and stereocilia (1,11,12).This study focuses on Myo7b, an unconventional myosin enriched in the microvilli of transporting epithelial cells (11, 13). Myo7b is characterized by a pair of MyTH4-FERM tandems in its tail cargo-binding domain. In addition to Myo7b, Myo7a, Myo10, and Myo15a also contain one or two MyTH4-FERM tandems in their tail domains (14). A common property of MyTH4-FERM myosins is their involvement in the formation or elongation/stabilization of actin-bundle support...

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“…Motins have also been implicated in a feed-forward loop that promotes Hippo pathway activation: Motins are substrates of LATS [83-86], and phosphorylation by LATS both stabilizes Motins, and promotes their binding to Merlin. Binding of Motins to Merlin appears to influence Merlin conformation, such that its binding to LATS is enhanced, which presumably promotes further LATS activation [87]. …”

Section: Dynamic Localization Of Hippo Pathway Componentsmentioning

confidence: 99%

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

Sun

Irvine

2016

Trends in Cell Biology

125

131

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The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo.

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Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway

Cited by 124 publications

References 62 publications

Characterization of Hippo Pathway Components by Gene Inactivation

Characterization of Hippo Pathway Components by Gene Inactivation

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

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