Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis

Wang, Yu; Zhu, Yuwen; Gu, Yuan; Ma, Mingyue; Wang, Yebin; Qi, Sixian; Zeng, Yan; Zhu, Rui; Yu, Pengcheng; Xu, Jiawei; Shu, Yilai; Yu, Fa‐Xing

doi:10.1016/j.celrep.2021.109596

Cited by 19 publications

(29 citation statements)

References 57 publications

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“…4d). We have previously shown that NF2 is involved in the establishment of tight junctions 28 . In NF2- deficient cells, the organization of tight junctions was significantly disrupted, which consequently reduced the tight junctional localization of KIRREL1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Wang

Sha

et al. 2022

Preprint

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Dysregulation of the Hippo tumor suppressor pathway and hyperactivation of YAP/TAZ are frequently observed in human cancers and represent promising therapeutic targets. However, strategies targeting the mammalian Hippo pathway are limited due to the lack of a well-established cell surface regulator. By combining protein interactome data and clinical data, we have identified transmembrane protein KIRREL1 as an upstream regulator of the Hippo pathway. KIRREL1 interacts with Hippo pathway components SAV1 and LATS1/2 via its intracellular C-terminal domain and promotes LATS1/2 activation by MST1/2 (Hippo kinases), in turn inhibiting YAP/TAZ activity and target gene expression. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. In mouse liver tumors driven by YAP activation, KIRREL1 protein is robustly induced. Moreover, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Finally, transgenic expression of KIRREL1 effectively blocked tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, suggesting an important role of KIRREL1 in inhibiting cancer development. Together, these findings indicate that KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway, and serves as a cell surface marker and potential drug target in cancers with YAP/TAZ dependency.

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Section: Resultsmentioning

confidence: 99%

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

Wang

Sha

et al. 2022

Preprint

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“…Recent data have shown that in NF2-null cells, Motin family members control YAP/TAZ activity and mediate the benign nature of most NF2-null tumour types. 67 Additionally, in one study of human schwannomas, Lats1 and Lats2 mutations were seen in only 2% and 1% of cases, respectively, compared to 55% showing mutations in the NF2 gene 68 ; it is therefore arguable that a schwannoma model with NF2 loss is more clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

Laraba

Guibert

Hewitt

et al. 2022

Brain

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Schwannoma tumours typically arise on the 8th cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the 8th or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

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“…Many genes upregulated in cancer are oncogenes, but this may not be a universal rule. For instance, AMOTL2 and AXIN2, which are targets of YAP and beta-catenin, respectively, are highly expressed in YAP-or beta-catenin-active cancers, but both AMOTL2 and AXIN2 have tumor-suppressor functions (Klaus and Birchmeier, 2008;Wang et al, 2021). Hence, KIRREL1 may represent a tumor-suppressor gene that is highly expressed in cancers.…”

Section: Discussionmentioning

confidence: 99%

“…However, the interaction between KIRREL1 and LATS1/2 or SAV1 was not dramatically changed (Figure 3C). We have previously shown that NF2 is involved in the establishment of cell-cell adhesions (Wang et al, 2021). In NF2-deficient cells, the organization of cell-cell adhesions was significantly disrupted, which consequently reduced the cell-cell adhesion localization of KIRREL1 (Figures S3A, S3G, and S3H).…”

Section: Identification Of Kirrel1 As a Negative Yap Regulatormentioning

confidence: 91%

Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis

Cited by 19 publications

References 57 publications

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

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

Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

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

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