Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers

Gu, Yuan; Wang, Yu; Sha, Zhao; He, Chenxi; Zhu, Yuwen; Li, Jian; Yu, Aijuan; Zhong, Zhenxing; Wang, Xuefei; Sun, Yihong; Lan, Fei; Yu, Fa-Xing

doi:10.1016/j.celrep.2022.111296

Cited by 10 publications

(4 citation statements)

References 66 publications

(72 reference statements)

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“…KIRREL1 knockout led to the activation of YAP. 107,108 Recently, integrated screens revealed KIRREL as a cell surface tumour suppressor involved in the Hippo pathway that could bind directly to SAV1 to activate this pathway. 109 In addition, it was shown that the palmitoylation of TEAD was also regulated by cell density.…”

Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

144

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As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

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Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

144

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“…Others have shown that the primary functional role of SAV1 is to anchor MST1/2 at the plasma membrane, where MST1/2 can phosphorylate LATS1/2. 54,55 In this model, however, it is not clear how nuclear YAP1 can translocate to the cytosol to meet LATS1/2 in the absence of mechanical force. The force-induced nuclear pore stretching model does not explain this mechanism.…”

Section: ■ Discussionmentioning

confidence: 98%

Identification of Filamin A Mechanobinding Partner III: SAV1 Specifically Interacts with Filamin A Mechanosensitive Domain 21

et al. 2023

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Filamin A (FLNA) cross-links actin filaments and mediates mechanotransduction by force-induced conformational changes of its domains. FLNA's mechanosensitive immunoglobulin-like repeats (R) interact with each other to create cryptic binding sites, which can be exposed by physiologically relevant mechanical forces. Using the FLNA mechanosensing domains as an affinity ligand followed by stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, we recently identified smoothelin and fimbacin as FLNA mechanobinding proteins. Here, using the mechanosensing domain as an affinity ligand and two labeled amino acids, we identify salvador homologue 1 (SAV1), a component of the Hippo pathway kinase cascade, as a new FLNA mechanobinding partner. We demonstrate that SAV1 specifically interacts with the cryptic C−D cleft of FLNA R21 and map the FLNA-binding site on SAV1. We show that point mutations on the R21 C strand block the SAV1 interaction and find that SAV1 contains a FLNA-binding motif in the central region ( 116 Phe− 124 Val). Point mutations F116A and T118A (FT/AA) disrupt the interaction. A proximity ligation assay reveals that their interaction occurs in the cytosol in an actin polymerization-dependent manner. Although SAV1 is typically found in the cytosol, disrupting the interaction between SAV1 and FLNA causes SAV1 to diffuse to the nucleus and YAP1 to diffuse to the cytosol in an inverse relationship. These results suggest that FLNA mediates regulation of the Hippo pathway through actin polymerizationdependent interaction with SAV1.

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“…Subsequently, LATS1/2 associates with the MST1/2-MOB1A/B complex, leading to LATS1/2 phosphorylation and activation by MST1/2 [25,26]. Additional proteins, including angiomotin (AMOT) [27,28], Kin of IRRE-like protein 1 (KIRREL1) [29][30][31], FAT1 [32], E-cadherin [33], leukemia inhibitory factor receptor (LIFR) [34], and Scribble [35], play similar roles by anchoring MST and LATS to the plasma membrane to sustain their activities. Notably, alterations of these proteins, such as NF2, E-cadherin, AMOT, and FAT1, are often observed in cancer and are associated with elevated YAP/TAZ activity [32,36,37].…”

Section: Advances In Upstream Regulators Of Hippo Signalingmentioning

confidence: 99%

New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

Zhao,

Sheldon,

Sun

et al. 2023

Cancers

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The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ’s biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.

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Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers

Cited by 10 publications

References 66 publications

The Hippo signalling pathway and its implications in human health and diseases

The Hippo signalling pathway and its implications in human health and diseases

Identification of Filamin A Mechanobinding Partner III: SAV1 Specifically Interacts with Filamin A Mechanosensitive Domain 21

New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

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