The Role of FBXW Subfamily of F-box Proteins in Tumorigenesis

H. Inuzuka and W. Wei, SCF and APC E3 Ubiquitin Ligases in Tumorigenesis, SpringerBriefs in Cancer Research, DOI 10.1007/978-3-319-05026-3_2, © The Author(s) 2014 Abstract In the human genome, 69 putative F-box proteins have been identifi ed which could form a variety of different SCF type E3 ligase complexes to specifi cally target a wide range of proteins for degradation. F-box proteins can be further subclassifi ed into three families largely based on the presence of three recognizable domains: WD repeats, leucine-rich repeats (LRR), and other types of protein interaction domains. The FBXW subfamily comprises ten proteins that contain both the F-box motif and the WD40 repeat domain, including FBXW-1 (also known as betatransducin repeat-containing protein and β-TRCP1), FBXW-2, FBXW-4, FBXW-5, FBXW-7, FBXW-8, FBXW-9, FBXW-10, FBXW11 (also known as β-TRCP2), and FBXW-12 (Fig. 2.1). Over the past 17 years, intensive research efforts have been devoted, using both mouse genetic models and biochemical approaches, to identify specifi c ubiquitin substrates for a given F-box protein, which have helped the scientifi c community to reveal the important contributions of F-box proteins including the three well-studied E3 ligases SCF Skp2 , SCF FBW7 , and SCF β-TRCP in human cancers (Welcker and Clurman, Nat Rev Cancer 8(2):83–93, 2008; Frescas and Pagano, Nat Rev Cancer 8(6):438– 449, 2008). Mechanistically, misregulated degradation of oncoproteins or tumor suppressors by various SCF E3 ligases could lead to tumorigenesis. Thus, F-box proteins could function as either oncoproteins or tumor suppressors, depending on the functional outputs of their ubiquitin substrates. In this chapter, we summarize the recent genetic, pathological, and biochemical evidence revealing a possible role for FBXW subfamily of F-box proteins in tumorigenesis. To this end, we focus our discussion on our current knowledge accumulated in three major categories: physiological evidence (genetically engineered Chapter 2 The Role of FBXW Subfamily of F-box Proteins in Tumorigenesis