Tumor suppressor Fbxw7 targets SIK2 for degradation to interfere TORC2-AKT signaling in pancreatic cancer.

: The tumor suppressor Fbxw7 (F-box/WD repeat-containing protein 7) is a substrate-recognition subunit of a ubiquitin ligase complex. We have previously proposed that Fbxw7 inhibited pancreatic cancer cell proliferation and invasion by targeting β-catenin. To identify other targets of Fbxw7 involved in pancreatic carcinogenesis, we screened the human protein database for Fbxw7 target candidates using the conserved Fbxw7 recognizing sequences. Twenty-three candidates are identified, including 5 known Fbxw7 targets and 2 cancer-related genes (SIK2 and ZMIZ1). We identified SIK2 (salt inducible kinase 2) as an Fbxw7 target for degradation by binding to the "TPPPS" motif of SIK2 in pancreatic cancer cells. We also demonstrate that SIK2 promoted proliferation and mitotic progression of pancreatic cancer cells. Moreover, endogenous Fbxw7 downregulates SIK2 protein level for controlling cell cycle progression, possibly by interfering the SIK2/TORC2/AKT signaling pathway to modulate p21 expression. Collectively, these data demonstrate that Fbxw7 targets the cell cycle controller-SIK2 for degradation, leading to disrupting the downstream TORC2-AKT signaling to inhibit pancreatic cancer cell proliferation and cell cycle progression. This article is protected by copyright. All rights reserved.