Kindlin-2 promotes Src-mediated tyrosine phosphorylation of androgen receptor and contributes to breast cancer progression

被引:6
|
作者
Ma, Luyao [1 ]
Tian, Yeteng [1 ]
Qian, Tao [1 ]
Li, Wenjun [1 ]
Liu, Chengmin [1 ]
Chu, Bizhu [2 ]
Kong, Qian [2 ]
Cai, Renwei [1 ]
Bai, Panzhu [1 ]
Ma, Lisha [1 ]
Deng, Yi [1 ]
Tian, Ruijun [2 ]
Wu, Chuanyue [3 ,4 ]
Sun, Ying [1 ]
机构
[1] Southern Univ Sci & Technol, Sch Life Sci, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen Key Lab Cell Microenvironm,Dept Biol, Shenzhen 518055, Peoples R China
[2] Southern Univ Sci & Technol, Dept Chem, Shenzhen 518055, Peoples R China
[3] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA
[4] Univ Pittsburgh, Canc Inst, Pittsburgh, PA 15260 USA
基金
中国国家自然科学基金;
关键词
MUTATIONAL PROCESSES; FAMILY KINASES; INVASION; CELLS; EXPRESSION; ADHESION; AMPLIFICATION; METASTASIS; ACTIVATION; CYCLIN-D1;
D O I
10.1038/s41419-022-04945-z
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Androgen receptor (AR) signaling plays important roles in breast cancer progression. We show here that Kindlin-2, a focal adhesion protein, is critically involved in the promotion of AR signaling and breast cancer progression. Kindlin-2 physically associates with AR and Src through its two neighboring domains, namely F1 and F0 domains, resulting in formation of a Kindlin-2-AR-Src supramolecular complex and consequently facilitating Src-mediated AR Tyr-534 phosphorylation and signaling. Depletion of Kindlin-2 was sufficient to suppress Src-mediated AR Tyr-534 phosphorylation and signaling, resulting in diminished breast cancer cell proliferation and migration. Re-expression of wild-type Kindlin-2, but not AR-binding-defective or Src-binding-defective mutant forms of Kindlin-2, in Kindlin-2-deficient cells restored AR Tyr-534 phosphorylation, signaling, breast cancer cell proliferation and migration. Furthermore, re-introduction of phosphor-mimic mutant AR-Y534D, but not wild-type AR reversed Kindlin-2 deficiency-induced inhibition of AR signaling and breast cancer progression. Finally, using a genetic knockout strategy, we show that ablation of Kindlin-2 from mammary tumors in mouse significantly reduced AR Tyr-534 phosphorylation, breast tumor progression and metastasis in vivo. Our results suggest a critical role of Kindlin-2 in promoting breast cancer progression and shed light on the molecular mechanism through which it functions in this process.
引用
收藏
页数:16
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