The STK38–XPO1 axis, a new actor in physiology and cancer

Martin, Alexandre Pj; Aushev, Vasily N.; Zalcman, Gérard; Camonis, Jacques

doi:10.1007/s00018-020-03690-w

Cited by 8 publications

(8 citation statements)

References 99 publications

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“…This would clearly demonstrate that cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Activation of the Hippo pathway was crucial to regulating the subcellular localization of YAP1; when the Hippo pathway was activated, the downstream classic molecule YAP1 was phosphorylated and could not enter the nucleus, and thus remained in the cytoplasm [ 3 , 10 , 52 , 53 ]. We used NPASS to screen 48 natural small‐molecule compounds related to the breast cancer cell lines MDA‐MB‐231, MDA‐MB‐468, and MCF7 (Supplementary Figure S3A ).…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Guo

Cui

et al. 2023

Cancer Communications

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Background Nuclear Yes1‐associated transcriptional regulator (YAP1) promotes tumor progression. However, the function of cytoplasmic YAP1 in breast cancer cells and its impact on the survival of breast cancer patients remain unclear. Our research aimed to explore the biological function of cytoplasmic YAP1 in breast cancer cells and the possibility of cytoplasmic YAP1 as a predictive marker of breast cancer survival. Methods We constructed cell mutant models, including NLS‐YAP15SA (nuclear localized), YAP1S94A (incapable of binding to the TEA domain transcription factor family) and YAP1S127D (cytoplasmic localized), and used Cell Counting Kit‐8 (CCK‐8) assays, 5‐ethynyl‐2’‐deoxyuridine (EdU) incorporation assays, and Western blotting (WB) analysis to detect cell proliferation and apoptosis. The specific mechanism of cytoplasmic YAP1‐mediated endosomal sorting complexes required for transport III (ESCRT‐III) assembly was studied by co‐immunoprecipitation, immunofluorescence staining, and WB analysis. Epigallocatechin gallate (EGCG) was used to simulate YAP1 retention in the cytoplasm in in vitro and in vivo experiments to study the function of cytoplasmic YAP1. YAP1 binding to NEDD4‐like E3 ubiquitin protein ligase (NEDD4L) was identified using mass spectrometry and was verified in vitro. Breast tissue microarrays were used to analyze the relationship between cytoplasmic YAP1 expression and the survival of breast cancer patients. Results YAP1 was mainly expressed in the cytoplasm in breast cancer cells. Cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Cytoplasmic YAP1 bound to the ESCRT‐III complex subunits charged multivesicular body protein 2B (CHMP2B) and vacuolar protein sorting 4 homolog B (VPS4B), promoting assembly of CHMP2B‐VPS4B and activating autophagosome formation. EGCG retained YAP1 in the cytoplasm, promoting the assembly of CHMP2B‐VPS4B to promote autophagic death of breast cancer cells. YAP1 bound to NEDD4L, and NEDD4L mediated ubiquitination and degradation of YAP1. Breast tissue microarrays revealed that high levels of cytoplasmic YAP1 were beneficial to the survival of breast cancer patients. Conclusions Cytoplasmic YAP1 mediated autophagic death of breast cancer cells by promoting assembly of the ESCRT‐III complex; furthermore, we established a new breast cancer survival prediction model based on cytoplasmic YAP1 expression.

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Section: Resultsmentioning

confidence: 99%

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Guo

Cui

et al. 2023

Cancer Communications

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“…Our data reveals that Caprin-1 induces the dephosphorylation of ULK1 and triggers autophagosome fusion that maintains cancer cells growth. STK38 is a Hippo pathway serine/threonine protein kinase with multifarious functions in cancers [ 41 , 42 ]. STK38 supports the interaction of Exo84 with Beclin1 and RalB which is required for the initiation of autophagosome [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer

Yang,

Chen,

et al. 2023

J Transl Med

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Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. Methods Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. Results Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. Conclusions Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.

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“…The other gene that could possibly explain an association between rs148413365 and CSFK is STK38. The STK38 protein was recently identified as part of the Hippo pathway and is able to inhibit YAP/TAZ signalling [ 53 ]. Deletion of LATS1/2, which has a similar effect on YAP/TAZ expression as STK38, leads to upregulated YAP/TAZ signalling and kidney agenesis, which could be rescued by reducing YAP/TAZ levels [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney

et al. 2022

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Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10−8, and variants in 30 loci reached the suggestive significance threshold of 1 × 10−5. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1, p-value = 1.4 × 10−8) on chromosome 7 was most promising due to its close proximity to HGF, a gene known to be involved in kidney development. Based on their known molecular functions, both KCTD20 and STK38 could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.

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The STK38–XPO1 axis, a new actor in physiology and cancer

Cited by 8 publications

References 99 publications

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer

A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney

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