Loss of KIBRA function activates EGFR signaling by inducing AREG

Abstract

The Hippo signaling pathway is a central regulator of organ size, tissue homeostasis, and tumorigenesis. KIBRA is a member of the WW domain-containing protein family and has recently been reported to be an upstream protein in the Hippo signaling pathway. However, the clinical significance of KIBRA deregulation and the underlying mechanisms by which KIBRA regulates breast cancer (BC) initiation and progression remain poorly understood. Here, we report that KIBRA knockdown in mammary epithelial cells induced epithelial-to-mesenchymal transition (EMT) and increased cell migration and tumorigenic potential. Mechanistically, we observed that inhibiting KIBRA induced growth factor-independent cell proliferation in 2D and 3D culture due to the secretion of amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand. Also, we show that AREG activation in KIBRA-knockdown cells depended on the transcriptional coactivator YAP1. Significantly, decreased expression of KIBRA is correlated with recurrence and reduced BC patient survival. In summary, this study elucidates the molecular events that underpin the role of KIBRA in BC. As a result, our work provides biological insight into the role of KIBRA as a critical regulator of YAP1-mediated oncogenic growth, and may have clinical potential for facilitating patient stratification and identifying novel therapeutic approaches for BC patients.

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

“…Hence, the reduced expression of Hippo core kinases in the +DDR/+COL1 HT1080 tumours may underlie the ability of these tumours to display accelerated growth. Consistent with the tumour suppressive role of the Hippo pathway, we found that KIBRA, an upstream regulator of the Hippo pathway, and also considered a tumour suppressor [150][151][152][153] , was significantly downregulated in +DDR2/+COL1 but not in +DDR1b/+COL1 tumours. This suggests that KIBRA may be a major target of DDR2 signalling in response to collagen in vivo.…”

Low expression of WWC1, a tumor suppressor gene, is associated with aggressive breast cancer and poor survival outcome

“…Loss of WWC1 function could also induce EMT and promote mammary epithelial cell transformation, whereas WWC1 overexpression was found to suppress head and neck squamous cell carcinoma cells in forming colony and oncosphere in soft agar [37]. Based on the findings, WWC1 was considered a potential tumor suppressor [38]. A recent study confirmed that WWC1 could inhibit breast tumor metastasis both in vitro and in vivo [6].…”

Hippo signaling pathway and respiratory diseases

“…By their WW domains, kidney and brain protein (KIBRA) is bound to Merlin, which is also known as neurofibromin 2 (NF2). Subsequently, the combination of KIBRA and Merlin recruits LATS1/2 to the cell membrane [ 41 – 43 ]. Meanwhile, the WW domain of the KIBRA binding to SAV results in the form of KIBRA/SAV heterodimer, which recruits MST1/2 to the cell membrane; thus the LATS1/2-HM is phosphorylated.…”

“…Meanwhile, the WW domain of the KIBRA binding to SAV results in the form of KIBRA/SAV heterodimer, which recruits MST1/2 to the cell membrane; thus the LATS1/2-HM is phosphorylated. Subsequently, phosphorylation of Ser127 in YAP interacts with 14-3-3 proteins to form a complex that remains in the cytoplasm, and the expression of target gene is also decreased [ 41 – 43 ]. It is reported angiomotin (AMOT) is associated with cell polarity, regulation of angiogenesis, cell migration, actin dynamics, and interaction with YAP [ 44 , 45 ].…”