Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis.

By Bin Zhao, Li Li, Lloyd H. Wang, Cun-Yu Wang, Jindan Yu, K. Guan. Genes & Development, 2012

752 citations recorded by the source corpus.

Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.

Subfields: Cell Biology

View Paper: https://www.semanticscholar.org/paper/57d60bdb8ee485bce986f2efb35adb1240094a6b

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. Bin Zhao
5. G. Halder
6. M. Cordenonsi
7. Randy L. Johnson
8. H. Park

Citations in the corpus

• YAP/TAZ at the roots of cancer (2016, background): “In turn, cytoskeletal inhibition is also reinforced by LATSmediated YAP phosphorylation (Aragona et al., 2013; Zhao et al., 2012).”
• The Hippo Pathway: Biology and Pathophysiology. (2019, background): “Notably, disruption of microtubules by nocodazole decreases YAP/TAZ phosphorylation, an effect opposite to F-actin disruption (89).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “(265) showed that cell detachment, a wellknown inducer of cell death by anoikis, induces cytoskeletal reorganization and induction of LATS activity; however, while YAP overexpression fully rescued detachment-induced anoikis, depletion of endogenous LAST1/2 did not, indicating that a combination of L”
• Alternative Wnt Signaling Activates YAP/TAZ (2015, background): “The Rho GTPase family is the major effector of Ga12/13 signaling, and also plays a critical role in both alternative Wnt signaling and Hippo-YAP/TAZ regulation (Schlessinger et al., 2009; Yu et al., 2012; Zhao et al., 2012).”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, neutral): “Supporting a role for LATS1/2, the phosphorylation status and in vitro kinase activity of LATS1/2 are clearly regulated upon actin cytoskeleton rearrangement, and the kinetics are similar to that of YAP/TAZ phosphorylation (Yu et al., 2012; Zhao et al., 2012).”
• The Hippo pathway: regulators and regulations. (2013, background): “Zhao et al. (2012) demonstrated that cell detachment and attachment could either repress or induce YAP/TAZ activity, respectively, and inhibition of YAP/ TAZ was involved in cell detachment-induced anoikis (a specific type of apoptosis).”
• The Hippo signaling pathway in stem cell biology and cancer (2014, positive): “Several studies have reported that YAP/TAZ is regulated by mechanical cues from neighboring cells and the extracellular matrix [50 – 52].”
• A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. (2013, positive): “…as ideal candidates: treatments that disrupt F-actin or cytoskeletal contractility oppose YAP/TAZ function (Dupont et al., 2011; Wada et al., 2011; Zhao et al., 2012); then, it is recognized that cells respond to external mechanical cues by adjusting the tension and overall organization of their…”
• The Hippo signalling pathway and its implications in human health and diseases (2022, background): “95 Moreover, it was shown that the activity of Rho plays a pivotal role in the cell attachment-dependent regulation of the Hippo pathway.”
• Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling (2012, background): “A role of actin cytoskeleton on the Hippo-YAP pathway has recently been suggested (Dupont et al., 2011; Fernández et al., 2011; Rauskolb et al., 2011; Sansores-Garcia et al., 2011; Zhao et al., 2012).”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “Cytoskeleton-mediated regulation of Yki/YAP/TAZ activity has been reported to involve both Wts/LATS-dependent (Fletcher et al., 2018; Meng et al., 2018; Plouffe et al., 2016; Rauskolb et al., 2014; Zhao et al., 2012; Zheng et al., 2015) and -independent mechanisms (Aragona et al.”
• Mechanisms of Hippo pathway regulation (2016, neutral): “Attachment of cells to ECM induces YAP nuclear localization through activation of Rho-GTPases or the FAK–Src–PI3K pathway (Zhao et al. 2012; Kim and Gumbiner 2015).”
• The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain (2012, background): “In addition, both increased YAP protein staining and reduced LATS mRNA levels are correlated with metastasis in human patients (3, 22).”
• The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment (2013, positive): “Here, the mechanical properties of the extracellular matrix and cell-matrix attachment regulate YAP/TAZ localization and activity, in a process that requires F-actin and that is also present in Drosophila 96–100 .”