Nucleolar Localization of the ErbB3 Receptor As a New Target in Glioblastoma

Overview

Journal BMC Mol Cell Biol

Publisher Biomed Central

Specialty Cell Biology

Date 2022 Mar 8

PMID 35255831

Authors

Marzia Tagliaferro

Paolo Rosa

Gian Carlo Bellenchi

Daniela Bastianelli

Rosa Trotta

Claudia Tito

Francesco Fazi

Antonella Calogero

Donatella Ponti

Affiliations

Soon will be listed here.

Abstract

Background: The nucleolus is a subnuclear, non-membrane bound domain that is the hub of ribosome biogenesis and a critical regulator of cell homeostasis. Rapid growth and division of cells in tumors are correlated with intensive nucleolar metabolism as a response to oncogenic factors overexpression. Several members of the Epidermal Growth Factor Receptor (EGFR) family, have been identified in the nucleus and nucleolus of many cancer cells, but their function in these compartments remains unexplored.

Results: We focused our research on the nucleolar function that a specific member of EGFR family, the ErbB3 receptor, plays in glioblastoma, a tumor without effective therapies. Here, Neuregulin 1 mediated proliferative stimuli, promotes ErbB3 relocalization from the nucleolus to the cytoplasm and increases pre-rRNA synthesis. Instead ErbB3 silencing or nucleolar stress reduce cell proliferation and affect cell cycle progression.

Conclusions: These data point to the existence of an ErbB3-mediated non canonical pathway that glioblastoma cells use to control ribosomes synthesis and cell proliferation. These results highlight the potential role for the nucleolar ErbB3 receptor, as a new target in glioblastoma.

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References

Thompson M, Lauderdale S, Webster M, Chong V, McClintock B, Saunders R . Widespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain. Brain Res. 2007; 1139:95-109. DOI: 10.1016/j.brainres.2006.11.047. View

Ma H, Pederson T . The nucleolus stress response is coupled to an ATR-Chk1-mediated G2 arrest. Mol Biol Cell. 2013; 24(9):1334-42. PMC: 3639045. DOI: 10.1091/mbc.E12-12-0881. View

Boisvert F, van Koningsbruggen S, Navascues J, Lamond A . The multifunctional nucleolus. Nat Rev Mol Cell Biol. 2007; 8(7):574-85. DOI: 10.1038/nrm2184. View

Auf G, Jabouille A, Delugin M, Guerit S, Pineau R, North S . High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor. BMC Cancer. 2013; 13:597. PMC: 3878670. DOI: 10.1186/1471-2407-13-597. View

Weeks S, Metge B, Samant R . The nucleolus: a central response hub for the stressors that drive cancer progression. Cell Mol Life Sci. 2019; 76(22):4511-4524. PMC: 6841648. DOI: 10.1007/s00018-019-03231-0. View

Ponti D, Carlo Bellenchi G, Puca R, Bastianelli D, Maroder M, Ragona G . The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis. PLoS One. 2014; 9(5):e96037. PMC: 4006901. DOI: 10.1371/journal.pone.0096037. View

Frogne T, Benjaminsen R, Sonne-Hansen K, Sorensen B, Nexo E, Laenkholm A . Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2008; 114(2):263-75. PMC: 2764248. DOI: 10.1007/s10549-008-0011-8. View

Giri D, Ali-Seyed M, Li L, Lee D, Ling P, Bartholomeusz G . Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol. 2005; 25(24):11005-18. PMC: 1316946. DOI: 10.1128/MCB.25.24.11005-11018.2005. View

Wang Z . ErbB Receptors and Cancer. Methods Mol Biol. 2017; 1652:3-35. DOI: 10.1007/978-1-4939-7219-7_1. View

10.

Naidu R, Yadav M, Nair S, Kutty M . Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer. 1998; 78(10):1385-90. PMC: 2063171. DOI: 10.1038/bjc.1998.689. View

11.

Bersaglieri C, Santoro R . Genome Organization in and around the Nucleolus. Cells. 2019; 8(6). PMC: 6628108. DOI: 10.3390/cells8060579. View

12.

Kancha R, von Bubnoff N, Duyster J . Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation. Cell Commun Signal. 2013; 11:39. PMC: 3726407. DOI: 10.1186/1478-811X-11-39. View

13.

Hayashi M, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J . High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res. 2008; 14(23):7843-9. DOI: 10.1158/1078-0432.CCR-08-1064. View

14.

Ruggero D, Pandolfi P . Does the ribosome translate cancer?. Nat Rev Cancer. 2003; 3(3):179-92. DOI: 10.1038/nrc1015. View

15.

Mi Y, Thomas S, Xu X, Casson L, Miller D, Bates P . Apoptosis in leukemia cells is accompanied by alterations in the levels and localization of nucleolin. J Biol Chem. 2002; 278(10):8572-9. DOI: 10.1074/jbc.M207637200. View

16.

Wang Y, Yamaguchi H, Hsu J, Hung M . Nuclear trafficking of the epidermal growth factor receptor family membrane proteins. Oncogene. 2010; 29(28):3997-4006. PMC: 2904849. DOI: 10.1038/onc.2010.157. View

17.

Ni C, Murphy M, Golde T, Carpenter G . gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001; 294(5549):2179-81. DOI: 10.1126/science.1065412. View

18.

Chen L, Chen J . MDM2-ARF complex regulates p53 sumoylation. Oncogene. 2003; 22(34):5348-57. DOI: 10.1038/sj.onc.1206851. View

19.

Andersen J, Lyon C, Fox A, Leung A, Lam Y, Steen H . Directed proteomic analysis of the human nucleolus. Curr Biol. 2002; 12(1):1-11. DOI: 10.1016/s0960-9822(01)00650-9. View

20.

Wolfson E, Solomon S, Schmukler E, Goldshmit Y, Pinkas-Kramarski R . Nucleolin and ErbB2 inhibition reduces tumorigenicity of ErbB2-positive breast cancer. Cell Death Dis. 2018; 9(2):47. PMC: 5833446. DOI: 10.1038/s41419-017-0067-7. View