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Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth
Galina Gritsina, … , Maha Hussain, Jindan Yu
Galina Gritsina, … , Maha Hussain, Jindan Yu
Published June 22, 2023
Citation Information: J Clin Invest. 2023;133(15):e166248. https://doi.org/10.1172/JCI166248.
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Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth

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Abstract

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

Authors

Galina Gritsina, Ka-wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu

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Figure 4

The CXCR7-ARRB2 protein complex interacts with AURKA.

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The CXCR7-ARRB2 protein complex interacts with AURKA.
(A) The whole lysa...
(A) The whole lysate of C4-2B-EnzR cells was subjected to anti-CXCR7 and IgG co-IP, followed by Western blot analyses. (B) ARRB2 increases CXCR7 and AURKA interaction. The 293T cells overexpressing Myc-AURKA, CXCR7-FLAG, and/or ARRB2-HA were subjected to co-IP with anti-FLAG antibodies, followed by Western blot. WCL, whole-cell lysate. (C) AURKA binds to the C-terminal domain (CTD) of ARRB2. 293T cells were cotransfected with Myc-AURKA and an empty vector, full-length (FL), N-terminal domain (NTD), or CTD of ARRB2. Co-IP was performed with an anti-HA antibody, followed by Western blot. (D) GST pull-down assay shows direct interaction between ARRB2 and AURKA. GST-ARRB2 FL, GST-ARRB2 CTD, or GST-GFP control proteins were incubated with FLAG-AURKA protein for 2 hours, separated by GSH-Sepharose, and resolved for Western blot. #, GST-GFP control band. (E) The CTD of ARRB2 restores CXCR7-AURKA interaction. The 293T-CXCR7 cells were transfected with the indicated plasmids and then subjected to co-IP using an anti-FLAG antibody, followed by Western blot analysis. (F) The kinase domain of AURKA binds to ARRB2. The 293T cells were cotransfected with ARRB2-HA and Myc-AURKA, FL, its regulatory (Reg), or kinase domain (Kin). Co-IP was performed with an anti-HA antibody, followed by WB analysis. (G) The kinase domain of AURKA forms a complex with CXCR7. CXCR7-FLAG construct was cotransfected in 293T cells with Myc-AURKA FL, regulatory domain (Reg), or kinase domain (Kin). Co-IP was performed with an anti-FLAG antibody, followed by Western blot. (H) ARRB2 KD decreases AURKA activation. C4-2B-CXCR7 cells were transfected with 2 independent siARRB2 for 48 hours and then analyzed by Western blot. Actin was used as a loading control. (I) A model depicting the interaction among the CXCR7-ARRB2-AURKA protein complex. Both the CTD and NTD of ARRB2 can interact with CXCR7, while only the CTD of ARRB2 binds to the kinase (Kin) domain of AURKA. The image was generated in BioRender. *, non-specific bands.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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