Cell surface nucleolin interacts with CXCR4 receptor via the 212 c-terminal portion

Abstract

Previously, we reported that CXCR4 receptor interacted with cell surface nucleolin, and the synergy of CXCR4 and nucleolin plays an essential role in malignant transformation. Here, we continued to conduct a structure-function analysis of nucleolin to identify which portion can efficaciously bind to CXCR4. In the present study, the expression of CXCR4 and nucleolin in 100 cases of papillary thyroid cancer (PTC) samples was investigated through immunohistochemistry (IHC). Subsequently, using nucleolin mutants and pull-down assay, we investigated precise interactions between CXCR4 and nucleolin in HEK-293 cells. A previous study demonstrated CXCR4 and nucleolin co-expressed in cell lines, and the present study further identified that CXCR4 and nucleolin co-expressed in PTC tissues, instead of normal tissues. The nucleolin mutant analysis revealed that nucleolin can efficaciously bind CXCR4 to activate CXCR4 signaling by 212 C-terminal domain. Conversely, N-terminal, RBD and GAR mutants of nucleolin showed no sign of activation of CXCR4 signaling, and differences were statistically insignificant (p > 0.05). In conclusion, these results suggested nucleolin is essential to activate CXCR4 signaling via 212 C-terminal domain, which is required for cell growth, migration, and invasiveness. Furthermore, nucleolin may interact with more G protein-coupled receptors, at least chemokine receptor. Our study will lay a new foundation for cancer therapy by antagonizing nucleolin and CXCR4.

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

“…Previous research has demonstrated that migration of A549 cells can be significantly inhibited by inhibiting the CC motif receptor 5/CC motif chemokine 5 axis (36). Studies have also demonstrated that the chemokine receptor CXCR4 interacts with nucleolin; nucleolin binds to CXCR4 via the C-terminal region, activates CXCR4 signaling and promotes tumor cell growth, metastasis, and migration (37,38). The interaction between nucleolin and the chemokine signaling pathway is interesting, and how nucleolin regulates chemokines and their receptors to promote cancer migration is worth further investigation.…”

The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy

“…Interestingly, recent evidence from co-immunoprecipitation studies indicated that NCL potentiates the SDF-1/CXCR4 axis by activating signalling downstream to the receptor. 41,42 We also reported that activation of the SDF-1/CXCR4 signalling pathway plays a role in the cardiovascular protective effects of LAV-BPIFB4 gene therapy in type 2 diabetic and atherosclerotic mice. 16,18…”

Anti-nucleolin aptamer AS1411: an advancing therapeutic

“…Nucleolin is overexpressed in non-small cell lung, gastric, ovarian, breast, and kidney cancers ( Masiuk et al, 2007 ; Cicchillitti et al, 2009 ; Qiu et al, 2013 ; Rosenberg et al, 2014 ; Xu et al, 2016 ). It can be found on the cell surface of HeLa cells, lymphoblastoid T-cells, breast carcinoma, hepatocarcinoma, laryngeal epithelial cells, and endothelial cells of angiogenic blood vessels ( Fogal et al, 2009 ; Fujiki et al, 2014 ; Koutsioumpa and Papadimitriou, 2014 ; Niu et al, 2015 ). Viruses such as Human immunodeficiency virus-1 (HIV-1), Respiratory syncytial virus (RSV), Influenza A, Parainfluenza virus 3, and Enterovirus 71 have all been shown to use nucleolin to enter a human host cell ( Bose et al, 2004 ; Su et al, 2015 ; Chan et al, 2016 ; Perrone et al, 2016 ; Mastrangelo et al, 2021 ).…”