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

Abstract

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.

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

“…Kindlin-2, a well-known focal adhesion protein, plays a crucial role in regulating integrin-dependent cellular events [23][24][25][26][27][28][29]. Recent studies have reported a role for Kindlin-2 precipitates in multiple integrinindependent pathways that modulate a series of cellular functions [30][31][32][33][34][35][36]. Kindlin-2 is essential for maintaining the hemostasis of many tissues and organs, including bone, renal glomerular, heart and smooth muscle [32,[36][37][38][39].…”

“…Kindlin-2 is essential for maintaining the hemostasis of many tissues and organs, including bone, renal glomerular, heart and smooth muscle [32,[36][37][38][39]. Kindlin-2 has been reported to be overexpressed in various cancers and depletion of Kindlin-2 effectively suppressed tumor progression [33,34,[40][41][42]. However, to date, it is not clear whether Kindlin-2 plays a role in pancreatic cancer development in vivo and if so, the underlying mechanisms remain to be investigated.…”

SRC kinase-mediated signaling pathways and targeted therapies in breast cancer

“…Among these substrates, SRC-mediated ER phosphorylation is necessary for ER binding to the estrogen response element and its subsequent dimerization [ 104 , 105 ]. While SRC-mediated AR phosphorylation is required for Kindlin-2-induced BC cell proliferation and migration in vitro and in vivo [ 106 ]. Based on these studies, the combination of endocrine therapy with SRC inhibitors may represent a treatment regimen in these subtypes of BC.…”

Kindlin-2 Regulates the Oncogenic Activities of Integrins and TGF-β In Triple Negative Breast Cancer Progression and Metastasis

“…Kindlin-2 regulates the growth and progression of breast cancer tumors by activating CSF-1-mediated macrophage in ltration, thereby promoting metastatic progression [16]. Its involvement extends to regulating tumor growth and progression by enhancing Wnt signaling through complex formation with β-catenin and TCF4, and contributing to Src-mediated tyrosine phosphorylation of androgen receptor [19] [20]. Therefore, Kindlin-2 has been established a major regulator of several hallmarks of cancer [21].…”