Phosphorylation of NF2 at Serine-13 by MAP4K family kinases mediates pathological angiogenesis

Ma, Mingyue; Zhong, Zhenxing; Zhu, Yuwen; Gu, Yuan; Jin, Ruxin; Meng, Zhipeng; Wang, Yu; Yu, Fa‐Xing

doi:10.1093/procel/pwac005

Cited by 3 publications

(4 citation statements)

References 15 publications

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“…Indeed, NF2 could interact strongly with LATS1/2 at endogenous levels (Fig 1G). Moreover, NF2 is a substrate of MAP4K1‐7, and weak interactions between NF2 and MAP4K2/4 had been detected in a coimmunoprecipitation assay using mild lysis buffer (Ma et al , 2022) (Fig EV2A and B). The interaction between NF2 and MAP4K4 required FERM domains on NF2 and both kinase and CNH domains in MAP4K4 (Fig EV2C and D).…”

Section: Resultsmentioning

confidence: 97%

“…MST1/2 and MAP4K1‐7 phosphorylate the hydrophobic motif of LATS1/2 in a redundant manner, which is critical for LATS1/2 activation (Li et al , 2014, 2015; Meng et al , 2015; Zheng et al , 2015). Moreover, MST1/2 and MAP4K1‐7 phosphorylate MOB1 at Thr35 (T35) and NF2 at Ser13 (S13), respectively (Meng et al , 2015; Ma et al , 2022) (Fig 1A). These findings indicate that MST1/2 and MAP4K1‐7 have overlapping and dedicated substrates (Fig 1B).…”

Section: Introductionmentioning

confidence: 99%

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Two Hippo signaling modules orchestrate liver size and tumorigenesis

Zhong

Zhu

et al. 2023

The EMBO Journal

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The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/ 2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Two Hippo signaling modules orchestrate liver size and tumorigenesis

Zhong

Zhu

et al. 2023

The EMBO Journal

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“…This suggests that these DEPs may be involved in wAMD development by activating kinase receptors, leading to pathological angiogenesis. Previous studies have shown that blocking the phosphorylation of kinase receptors can reduce CNV, − such as FGFR1 and VEGFR2. GO-CC analysis revealed that these DEPs were primarily enriched in the collagen-containing extracellular matrix, secretory granule lumen, and endoplasmic reticulum lumen.…”

Section: Resultsmentioning

confidence: 99%

Olink Profiling of Aqueous Humor Identifies Novel Biomarkers for Wet Age-Related Macular Degeneration

Liu,

Zhang,

Zhang

et al. 2024

J. Proteome Res.

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“…The MAP4K-mediated non-canonical Hippo signaling pathway is a molecular cascade that diverges from the classical Hippo pathway mediated by MST1/2. The biological roles of this MAP4K-Hippo signaling pathway have recently been implicated in the mouse models [26][27][28], and key Hippo components (SAV1, NF2, KIBRA) have thus been re-stra[fied (Hpo 1 vs. Hpo 2) [26].…”

Section: Rap2 Is a Required Component Of The Map4k-mediated Non-canon...mentioning

confidence: 99%

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation

Wu,

Cai,

Wang

et al. 2023

Preprint

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The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo kinase cascade activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signalingviaactivating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivtion. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.

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Phosphorylation of NF2 at Serine-13 by MAP4K family kinases mediates pathological angiogenesis

Cited by 3 publications

References 15 publications

Two Hippo signaling modules orchestrate liver size and tumorigenesis

Two Hippo signaling modules orchestrate liver size and tumorigenesis

Olink Profiling of Aqueous Humor Identifies Novel Biomarkers for Wet Age-Related Macular Degeneration

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation

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