The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer
- Author(s)
- Yang, X; Cruz, MI; Nguyen, EV; Huang, C; Schittenhelm, RB; Luu, J; Cowley, KJ; Shin, SY; Nguyen, LK; Lim Kam Sian, TCC; Clark, KC; Simpson, KJ; Ma, X; Daly, RJ;
- Journal Title
- Oncogene
- Publication Type
- Research article
- Abstract
- We have determined that expression of the pseudokinase NRBP1 positively associates with poor prognosis in triple negative breast cancer (TNBC) and is required for efficient migration, invasion and proliferation of TNBC cells in culture as well as growth of TNBC orthotopic xenografts and experimental metastasis. Application of BioID/MS profiling identified P-Rex1, a known guanine nucleotide exchange factor for Rac1, as a NRBP1 binding partner. Importantly, NRBP1 overexpression enhanced levels of GTP-bound Rac1 and Cdc42 in a P-Rex1-dependent manner, while NRBP1 knockdown reduced their activation. In addition, NRBP1 associated with P-Rex1, Rac1 and Cdc42, suggesting a scaffolding function for this pseudokinase. NRBP1-mediated promotion of cell migration and invasion was P-Rex1-dependent, while constitutively-active Rac1 rescued the effect of NRBP1 knockdown on cell proliferation and invasion. Generation of reactive oxygen species via a NRBP1/P-Rex1 pathway was implicated in these oncogenic roles of NRBP1. Overall, these findings define a new function for NRBP1 and a novel oncogenic signalling pathway in TNBC that may be amenable to therapeutic intervention.
- Publisher
- Springer Nature
- Keywords
- Humans; *Triple Negative Breast Neoplasms; rac1 GTP-Binding Protein/metabolism; Signal Transduction; Guanine Nucleotide Exchange Factors/metabolism; Cell Movement; Receptors, Cytoplasmic and Nuclear/metabolism; Vesicular Transport Proteins/metabolism
- Department(s)
- Laboratory Research
- PubMed ID
- 36693952
- Publisher's Version
- https://doi.org/10.1038/s41388-023-02594-w
- Open Access at Publisher's Site
https://doi.org/10.1038/s41388-023-02594-w- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-15 07:24:59
Last Modified: 2023-06-15 07:25:48