NMMHC-IIA-dependent nuclear location of CXCR4 promotes migration and invasion in renal cell carcinoma

Xu, Zhipeng; Li, Peng; Wei, Dan; Wang, Zhixiang; Bao, Yi; Sun, Jian; Qu, Le; Wang, Linhui

doi:10.3892/or.2016.5082

Cited by 27 publications

(21 citation statements)

References 36 publications

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“…A bioinformatics analysis using PSORTII NLS prediction software revealed a putative NLS-RPRK-between amino acids 146–149 within the CXCR4 sequence. This NLS was reported to play an important role in CXCR4 nuclear localization [15, 18]. Therefore, we mutated this NLS sequence to “AAAA” (CXCR4-mNLS), rendering the protein unable to localize to the nucleus (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We observed CXCR4 nuclear localization in RCC cells following CXCL12 stimulation, and this localization promoted RCC metastasis [16–18]. CXCR4 nuclear localization may play an important role in RCC metastasis by activating nuclear signaling pathways; this hypothesis is supported by the results of our previous study which identified a nuclear localization sequence (NLS) in CXCR4 [18]. However, the mechanisms of CXCR4 nuclear localization and the signaling pathways downstream of CXCR4 nuclear localization have not been elucidated.…”

Section: Introductionmentioning

confidence: 83%

“…Nuclear CXCR4 expression has been observed in several malignant tumors, such as breast cancer [10, 11], colorectal cancer [12], pancreatic adenocarcinoma [13], thyroid carcinoma [14], and prostate cancer [15]. We observed CXCR4 nuclear localization in RCC cells following CXCL12 stimulation, and this localization promoted RCC metastasis [16–18]. CXCR4 nuclear localization may play an important role in RCC metastasis by activating nuclear signaling pathways; this hypothesis is supported by the results of our previous study which identified a nuclear localization sequence (NLS) in CXCR4 [18].…”

Section: Introductionmentioning

confidence: 91%

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A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis

et al. 2018

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CXC chemokine receptor 4 (CXCR4) has been suggested to play a critical role in cancer metastasis. Some studies have described CXCR4 nuclear localization in metastatic lesions of renal cell carcinoma (RCC), which has been suggested to be correlated with cancer metastasis. However, the underlying mechanism and clinical significance of CXCR4 nuclear localization remains unknown. Here, we show that CXCR4 nuclear localization is more likely to occur in RCC tissues, especially in metastases, and is associated with poor prognosis. CXCR4 nuclear localization requires its nuclear localization sequence (NLS, residues 146-RPRK-149). After the mutation of NLS in CXCR4, CXCR4 nuclear localization in RCC cells is lost. Nuclear localization of CXCR4 promoted RCC tumorigenicity both in vitro and in vivo. Mechanistically, we found that CXCR4 and hypoxia-inducible factor-1α (HIF-1α) colocalized in RCC cells and interacted with each other. Moreover, CXCR4 nuclear localization promoted nuclear accumulation of HIF-1α, thereby promoting the expression of genes downstream of HIF-1α. Reciprocally, nuclear HIF-1α promoted CXCR4 transcription, thus forming a feed-forward loop. Subcellular CXCR4 and HIF-1α expression levels were independent adverse prognostic factors and could be combined with TNM stage to generate a predictive nomogram of the clinical outcome of patients with RCC. Therefore, our findings indicate that CXCR4 nuclear translocation plays a critical role in RCC metastasis and may serve as a prognostic biomarker and potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 91%

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A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis

et al. 2018

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“…Moreover, higher expression levels of MYH9 in nonepithelioid tumors were associated with significantly worse survival ( De Rienzo et al 2016 ). Curiously, MYH9 was shown to interact with CXCR4 by immunoprecipitation, mediating nuclear translocation of CXCR4 and resulting in metastatic behavior of renal cell carcinoma via its effects on cell migration and invasion ( Xu et al 2016 ). Previous studies also support an active role of MYH9 in angiogenesis; it serves as a physical linker between the cytoskeleton and nucleolin, mediating translocation of nucleolin during VEGF-directed angiogenesis ( Huang et al 2006 ).…”

Section: Discussionmentioning

confidence: 99%

De novo MYH9 mutation in congenital scalp hemangioma

Fomchenko

Durán

Jin

et al. 2018

Cold Spring Harb Mol Case Stud

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Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation (z score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo MYH9 mutation with congenital hemangioma.

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“…However, the biological mechanism of nuclear location of CXCR4 remains unclear. Non-muscle myosin heavy chain-IIA (NMMHC-IIA) has been identified as a nuclear CXCR4-interacting protein and pharmaceutical inhibition of NMMHC-IIA dampenes the nuclear translocation of CXCR4, as well as the metastatic capacity of renal carcinoma cells [38]. …”

Section: Chemokine Receptor Cysteinementioning

confidence: 99%

Intranuclear Signaling Cascades Triggered by Nuclear GPCRs

Cattaneo¹,

Parisi²,

Fioretti³

et al. 2016

J Cell Signal

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G protein-couped receptors (GPCRs) play a key role on cellular membranes, where they respond to a broad array of extracellular signals such as lipids, peptides, proteins and sensory agents. Intracellular biological responses triggered by these receptors include hormone secretion, muscle contraction, cellular metabolism a tyrosine kinase receptors transactivation. Recent results indicate that GPCRs localize to and signal also at nuclear level, thus regulating distinct signaling pathways which can also result from the integration of extracellular and intracellular stimuli. Nuclear GPCRs play a central role in many cellular processes, including regulation of gene transcription, cellular proliferation, neovascularization and RNA synthesis. On nuclear membranes and in nucleoplasm are present all the downstream signal transduction components of GPCRs, including G proteins, adenylyl cyclase, and second messengers such as Ca ++ , ERKs, p38MAPK and other protein kinases. Nuclear GPCRs may be constitutively active or may be activated by ligands internalized from the extracellular space or synthesized within the cell. The translocation of membrane receptors to the nucleus could be attributed to the presence of a Nuclear Localization Signal, which is present in the eighth helix or in the third intracellular loop of a limited number of GPCRs. However, several sequence motifs that do not resemble classical Nuclear Localization Signals can promote import of GPCRs. In this review we discuss the most recent results on nuclear localization and signaling of several GPCRS.

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NMMHC-IIA-dependent nuclear location of CXCR4 promotes migration and invasion in renal cell carcinoma

Cited by 27 publications

References 36 publications

A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis

A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis

De novo MYH9 mutation in congenital scalp hemangioma

Intranuclear Signaling Cascades Triggered by Nuclear GPCRs

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