{"title":"Histidine phosphorylation of NME1 regulates the Hippo pathway via the ARHGAP17-CDC42-cytoskeleton axis.","authors":"Xian Liu, Zhongnan Chen, Jianxi Zhu, Shengcheng Deng, Zhifen Zhou, Wenbin Ma, Zhou Songyang","doi":"10.1093/lifemedi/lnag002","DOIUrl":null,"url":null,"abstract":"<p><p><b>NME1 is a key metastasis suppressor whose activity depends on histidine phosphorylation, yet the biological significance of this modification remains poorly understood. Here, we reveal a previously unrecognized role for NME1 in regulating the Hippo pathway. Using PhastID-based proximity labeling combined with functional assays, we demonstrate that NME1 modulates CDC42 activity via ARHGAP17, a GTPase-activating protein, thereby influencing cytoskeletal organization and Hippo activation. Loss of NME1 reduced YAP phosphorylation and promoted its nuclear localization, indicating suppression of Hippo signaling. These findings define a histidine phosphorylation-dependent NME1-ARHGAP17-CDC42-cytoskeleton axis that controls the Hippo pathway, providing new insights into the functional repertoire of NME1 in cancer and development</b>.</p>","PeriodicalId":74073,"journal":{"name":"Life medicine","volume":"5 1","pages":"lnag002"},"PeriodicalIF":6.0000,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13070683/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/lifemedi/lnag002","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/2/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
NME1 is a key metastasis suppressor whose activity depends on histidine phosphorylation, yet the biological significance of this modification remains poorly understood. Here, we reveal a previously unrecognized role for NME1 in regulating the Hippo pathway. Using PhastID-based proximity labeling combined with functional assays, we demonstrate that NME1 modulates CDC42 activity via ARHGAP17, a GTPase-activating protein, thereby influencing cytoskeletal organization and Hippo activation. Loss of NME1 reduced YAP phosphorylation and promoted its nuclear localization, indicating suppression of Hippo signaling. These findings define a histidine phosphorylation-dependent NME1-ARHGAP17-CDC42-cytoskeleton axis that controls the Hippo pathway, providing new insights into the functional repertoire of NME1 in cancer and development.
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