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Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Published January 28, 2019
Citation Information: J Clin Invest. 2019;129(3):972-987. https://doi.org/10.1172/JCI122779.
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Research Article Oncology

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

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Abstract

Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1–/– Trp53–/– SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin β1, which stabilized integrin β1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

Authors

Gaoxiang Zhao, Liyan Gong, Dan Su, Yujuan Jin, Chenchen Guo, Meiting Yue, Shun Yao, Zhen Qin, Yi Ye, Ying Tang, Qibiao Wu, Jian Zhang, Binghai Cui, Qiurong Ding, Hsinyi Huang, Liang Hu, Yuting Chen, Peiyuan Zhang, Guohong Hu, Luonan Chen, Kwok-Kin Wong, Daming Gao, Hongbin Ji

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Figure 4

The CUL5-SOCS3 E3 ubiquitin ligase complex promotes integrin β1 ubiquitination and degradation.

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The CUL5-SOCS3 E3 ubiquitin ligase complex promotes integrin β1 ubiquiti...
(A) HeLa cells infected with the indicated shRNA were subjected to IB analysis. Tubulin served as a loading control. (B–E) Hela cells transfected with shCUL5 or shSOCS3 were treated with 100 μg/ml CHX prior to IB analysis. Tubulin served as a loading control. Integrin β1 protein levels were quantified by normalization to tubulin. (F) HEK293T cells transfected with Flag-ITGB1, His-tagged Ub (K11 or the K11R mutant), or HA-SOCS3 were treated with 10 μM MG132 for 10 hours before co-IP and IB analyses. (G) HEK293T cells transfected with WT integrin β1 or various lysine-to-arginine (K-R) mutants of integrin β1 were treated with 10 μM MG132 for 10 hours before co-IP and IB analyses. EV, empty vector. (H) Scheme illustrating how the CUL5-SOCS3 E3 ligase complex results in integrin β1 ubiquitination and degradation.
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