PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase

Abstract

Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.

USP7 promotes non‐small‐cell lung cancer cell glycolysis and survival by stabilizing and activating c‐Abl

“…Previous studies have demonstrated that c‐Abl has three NLS domains and one NES domain, which leads to c‐Abl shuttle between nuclei and cytoplasm, therefore displaying different functions 34 . Nuclear c‐Abl displays pro‐apoptotic activity upon DNA damage, 35 while cytoplasmic c‐Abl is oncogenic by activating a series of oncoprotein substrates including STAT3 signalling 7,24,36 . Although it is known that the chaperone protein 14‐3‐3α/β binds to c‐Abl and arrests it in cytosol, but the detailed mechanism is not well known.…”

“… 34 Nuclear c‐Abl displays pro‐apoptotic activity upon DNA damage, 35 while cytoplasmic c‐Abl is oncogenic by activating a series of oncoprotein substrates including STAT3 signalling. 7 , 24 , 36 Although it is known that the chaperone protein 14‐3‐3α/β binds to c‐Abl and arrests it in cytosol, but the detailed mechanism is not well known. In the present study, we found the underlying mechanism is probably also associated with the stabilization and the binding of 14‐3‐3α/β to c‐Abl induced by USP7.…”

Liver Kinase B1 Mediates Its Anti-Tumor Function by Binding to the N-Terminus of Malic Enzyme 3

“…The co-immunoprecipitation (co-IP) assays were performed as previously described ( Kang et al ., 2022 ). Briefly, cells were trypsinized, centrifuged, and the pellets were washed with cold phosphate-buffered saline and resuspended in lysis buffer [50 mM Tris-HCl pH 7.2, 150 mM NaCl, 1% Triton X-100, and a protease inhibitor cocktail containing 1 µg/mL leupeptin, 1 µg/mL pepstatin, 2 µg/mL aprotinin, and 200 µg/mL phenylmethylsulfonyl fluoride (PMSF)].…”

LKB1/STK11 Tumor Suppressor Reduces Angiogenesis by Directly Interacting with VEGFR2 in Tumorigenesis

“…Cell migration was assessed using Transwell chambers (8-mm pore size; Corning Costar, Cambridge, MA, USA) as described previously ( Kang et al ., 2022 ).…”