O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.

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YAP activates the Hippo pathway in a negative feedback loop

Cell Research ◽

10.1038/cr.2015.101 ◽

2015 ◽

Vol 25 (10) ◽

pp. 1175-1178 ◽

Cited By ~ 31

Author(s):

Xiaoming Dai ◽

Huan Liu ◽

Shuying Shen ◽

Xiaocan Guo ◽

Huan Yan ◽

...

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Hippo Pathway ◽

Negative Feedback Loop ◽

The Hippo Pathway

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Erratum: YAP activates the Hippo pathway in a negative feedback loop

Cell Research ◽

10.1038/cr.2017.96 ◽

2017 ◽

Vol 27 (8) ◽

pp. 1073-1073 ◽

Cited By ~ 4

Author(s):

Xiaoming Dai ◽

Huan Liu ◽

Shuying Shen ◽

Xiaocan Guo ◽

Huan Yan ◽

...

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Hippo Pathway ◽

Negative Feedback Loop ◽

The Hippo Pathway

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A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma

Cancer Research ◽

10.1158/0008-5472.can-18-2357 ◽

2018 ◽

Vol 79 (3) ◽

pp. 534-545 ◽

Cited By ~ 9

Author(s):

Shi-Lu Chen ◽

Chris Zhiyi Zhang ◽

Li-Li Liu ◽

Shi-Xun Lu ◽

Ying-Hua Pan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Growth ◽

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop

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Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

10.1101/2020.12.21.423274 ◽

2020 ◽

Author(s):

Adithya Chedere ◽

Kishore Hari ◽

Saurav Kumar ◽

Annapoorni Rangarajan ◽

Mohit Kumar Jolly

Keyword(s):

Breast Cancer ◽

Phenotypic Plasticity ◽

Cancer Cells ◽

Cell Population ◽

Negative Feedback ◽

Feedback Loop ◽

Phenotypic Switching ◽

Negative Feedback Loop ◽

Double Negative ◽

Protein Levels

AbstractAdaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.

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The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development

Development ◽

10.1242/dev.125.22.4417 ◽

1998 ◽

Vol 125 (22) ◽

pp. 4417-4425 ◽

Cited By ~ 6

Author(s):

M. Takahashi ◽

K. Tamura ◽

D. Buscher ◽

H. Masuya ◽

S. Yonei-Tamura ◽

...

Keyword(s):

Negative Feedback ◽

Limb Development ◽

Feedback Loop ◽

Limb Bud ◽

Negative Regulator ◽

Negative Feedback Loop ◽

Vertebrate Limb ◽

Limb Outgrowth ◽

Vertebrate Limb Development

We have determined that Strong's Luxoid (lstJ) [corrected] mice have a 16 bp deletion in the homeobox region of the Alx-4 gene. This deletion, which leads to a frame shift and a truncation of the Alx-4 protein, could cause the polydactyly phenotype observed in lstJ [corrected] mice. We have cloned the chick homologue of Alx-4 and investigated its expression during limb outgrowth. Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud. Local application of Sonic hedgehog (Shh) and Fibroblast Growth Factor (FGF), in addition to ectodermal apical ridge removal experiments suggest the existence of a negative feedback loop between Alx-4 and Shh during limb outgrowth. Analysis of polydactylous mutants indicate that the interaction between Alx-4 and Shh is independent of Gli3, a negative regulator of Shh in the limb. Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth.

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A Negative Feedback Loop Between NAMPT and TGF-β Signaling Pathway in Colorectal Cancer Cells

OncoTargets and Therapy ◽

10.2147/ott.s282367 ◽

2021 ◽

Vol Volume 14 ◽

pp. 187-198

Author(s):

Xiaoqun Lv ◽

Jinguo Zhang ◽

Jun Zhang ◽

Wencai Guan ◽

Weifang Ren ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Negative Feedback ◽

Feedback Loop ◽

Negative Feedback Loop ◽

Colorectal Cancer Cells

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Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

10.1101/2020.07.08.192765 ◽

2020 ◽

Author(s):

Sherzod A. Tokamov ◽

Ting Su ◽

Anne Ullyot ◽

Richard G. Fehon

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Hippo Pathway ◽

Tissue Growth ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

The Core ◽

Pathway Activation ◽

The Hippo Pathway ◽

Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

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