FBW7-mediated ubiquitination and degradation of KLF5

Abstract

Krüppel-like factor (KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF proteins is important for their transcriptional activities and biological functions. One KLF family member with important roles in cell proliferation and tumorigenesis is KLF5. The function of KLF5 is tightly controlled by post-translational modifications, including SUMOylation, phosphorylation, and ubiquitination. Recent studies from our lab and others' have demonstrated that the tumor suppressor FBW7 is an essential E3 ubiquitin ligase that targets KLF5 for ubiquitination and degradation. KLF5 contains functional Cdc4 phospho-degrons (CPDs), which are required for its interaction with FBW7. Mutation of CPDs in KLF5 blocks the ubiquitination and degradation of KLF5 by FBW7. The protein kinase Glycogen synthase kinase 3β is involved in the phosphorylation of KLF5 CPDs. In both cancer cell lines and mouse models, it has been shown that FBW7 regulates the expression of KLF5 target genes through the modulation of KLF5 stability. In this review, we summarize the current progress on delineating FBW7-mediated KLF5 ubiquitination and degradation.

Keywords: Degradation; FBW7; Krüppel-like factor 5; Krüppel-like factor family; Ubiquitin proteasome system.

Figure 1

Regulation of gene expression by Krüppel-like factor 5. VEGF: Vascular endothelial growth factor; MCP-1: Monocyte chemoattractant protein-1; NK-κB: Nuclear factor κB; MMP-9: Matrix metalloproteinase-9; PAI-1: Plasminogen activator inhibitor-1; iNOS: Inducible nitric oxide synthase.

Figure 2

A model for FBW7 mediated Krüppel-like factor 5 degradation. SCFFBW7 recognizes KLF5 via conserved Cdc4 phospho-degron (CPD) in KLF5, GSK3 phosphorylates the threonine of the CPD, which facilitates the degradation of KLF5. FBW7 plays an important role in tumor suppression via targeting numerous oncoproteins for degradation, such as Myc, cyclin E, mammalian target of rapamycin (Mtor), Mcl-1, and so on. KLF5 has an important role in regulating cellular functions, including promoting cell proliferation, cell cycle, and embryonic stem cell (ESC) self-renewal. FBW7 promotes KLF5 ubiquitination and degradation through 26S proteasome. KLF: Krüppel-like factor.