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

• Published in: Cell death & disease Vol. 13; no. 5; p. 482
• Main Authors: Ma, Luyao, Tian, Yeteng, Qian, Tao, Li, Wenjun, Liu, Chengmin, Chu, Bizhu, Kong, Qian, Cai, Renwei, Bai, Panzhu, Ma, Lisha, Deng, Yi, Tian, Ruijun, Wu, Chuanyue, Sun, Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.05.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 14; 631/67/1347; 631/80/86; 96; Androgen receptors; Androgens; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Culture; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Defective mutant; Female; Humans; Immunology; Kinases; Life Sciences; Membrane Proteins; Metastases; Mice; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neoplasm Proteins; Phosphorylation; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction; Src protein; Tumors; Tyrosine; Tyrosine - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04945-z

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.