UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer

Sane, Sanam; Srinivasan, Rekha; Potts, Rashaun; Eikanger, Morgan; Zagirova, Diana; Freeling, Jessica; Reihe, Casey; Antony, Ryan; Gupta, Brij K.; Lynch, Douglas; Bleeker, Jonathan; Turaihi, Hassan; Pillatzki, Angela; Zhou, Wei; Luo, Xu; Linnebacher, Michael; Agany, Diing D.M.; Zohim, Etienne Gnimpieba; Humphrey, Lisa E.; Black, Adrian R.; Rezvani, Khosrow

doi:10.1038/s41388-023-02686-7

Cited by 4 publications

(2 citation statements)

References 87 publications

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“…Neogenin inhibits CRC progression and metastasis by binding to Merlin and subsequently enhances YAP phosphorylation [43]. UBXN2A inhibits CRC growth and metastasis by reducing AKT phosphorylation downstream of the dominant oncogenic pathway in CRC [44]. As for non-coding RNAs, linc00152 can block CK1-mediated cytoplasmic β-catenin phosphorylation and consequently facilitate β-catenin nuclear translocation, thus promoting colon cancer EMT and metastasis [45].…”

Section: Phosphorylation Regulates Emtmentioning

confidence: 99%

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Peng,

Liu,

Hai

et al. 2024

Cancers

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Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. CRC metastasis is a multi-step process with various factors involved, including genetic and epigenetic regulations, which turn out to be a serious threat to CRC patients. Post-translational modifications (PTMs) of proteins involve the addition of chemical groups, sugars, or proteins to specific residues, which fine-tunes a protein’s stability, localization, or interactions to orchestrate complicated biological processes. An increasing number of recent studies suggest that dysregulation of PTMs, such as phosphorylation, ubiquitination, and glycosylation, play pivotal roles in the CRC metastasis cascade. Here, we summarized recent advances in the role of post-translational modifications in diverse aspects of CRC metastasis and its detailed molecular mechanisms. Moreover, advances in drugs targeting PTMs and their cooperation with other anti-cancer drugs, which might provide novel targets for CRC treatment and improve therapeutic efficacy, were also discussed.

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Section: Phosphorylation Regulates Emtmentioning

confidence: 99%

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Peng,

Liu,

Hai

et al. 2024

Cancers

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“…Recently, Sane et al. identified a new tumour suppressor in colorectal cancer called UBXN2A, capable of suppressing the mTORC2 signaling pathway via the ubiquitination of RICTOR for 26S proteasomal degradation, without effect on mTORC1 66 . These data highlight the importance of mTORC2 in colorectal cancer and the therapeutic potential of selective anti‐mTORC2 drugs for these tumours.…”

Section: Sin1 and Cancersmentioning

confidence: 99%

Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2

Ezine,

Lebbe,

Dumaz

2023

Clinical & Translational Med

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BackgroundAlthough the PI3K/AKT/mTOR pathway is one of the most altered pathways in human tumours, therapies targeting this pathway have shown numerous adverse effects due to positive feedback paradoxically activating upstream signaling nodes. The somewhat limited clinical efficacy of these inhibitors calls for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.Main bodyRecent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro‐tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial‐mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK.ConclusionTherefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.

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mTORC2: A neglected player in aging regulation

Xu,

Chen,

Xiao

2024

Journal Cellular Physiology

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Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro‐proliferative factor and a pro‐aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.

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UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer

Cited by 4 publications

References 87 publications

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2

mTORC2: A neglected player in aging regulation

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