Journal
CELL DEATH & DISEASE
Volume 13, Issue 5, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-022-04945-z
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Funding
- National Natural Science Foundation of China [82070728, 81900632, 81772983]
- Natural Science Foundation of Guangdong Province [2020A1515011305, 2121B1515120063, 2017B030301018]
- Shenzhen Innovation Committee of Science and Technology, China [JCYJ20190809141003834, JCYJ20200109141212325]
- Stable Support Plan Program of Shenzhen Natural Science Fund [GXWD20201230110313001, 20200925153241002]
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Kindlin-2 is found to be crucial for promoting AR signaling and breast cancer progression. It physically associates with AR and Src, forming a complex that facilitates Src-mediated AR Tyr-534 phosphorylation and signaling, leading to enhanced breast cancer cell proliferation and migration. Depletion of Kindlin-2 suppresses AR signaling, resulting in diminished breast cancer progression.
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.
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