Role of the ubiquitin ligase Fbw7 in cancer progression

Abstract

Fbw7 is a member of F-box family proteins, which constitute one subunit of Skp1, Cul1, and F-box protein (SCF) ubiquitin ligase complex. SCF(Fbw7) targets a set of well-known oncoproteins, including c-Myc, cyclin E, Notch, c-Jun, and Mcl-1, for ubiquitylation and degradation. Fbw7 provides specificity of the ubiquitylation of these substrate proteins via recognition of a consensus phosphorylated degron. Through regulation of several important proteins, Fbw7 controls diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and neural cell stemness. As reduced Fbw7 expression level and loss-of-function mutations are found in a wide range of human cancers, Fbw7 is generally considered as a tumor suppressor. However, the exact mechanisms underlying Fbw7-induced tumor suppression is unclear. This review focuses on regulation network, biological functions, and genetic alteration of Fbw7 in connection with its role in cancer development.

Targeting FBW7 as a Strategy to Overcome Resistance to Targeted Therapy in Non–Small Cell Lung Cancer

“…Another important aspect of substrate binding lies in the notion that the substrate needs to be phosphorylated within the CDC4 phosphodegron (CPD) motif before binding to FBW7 (31,32). In support of this notion, MCL-1 dephosphorylated by l-phosphatase failed to coprecipitate with FBW7 ( Supplementary Fig.…”

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“…Importantly, FBW7 is considered as a tumor suppressor protein in large due to the fact that FBW7 targets multiple well-known oncoproteins including Cyclin E [2,[6][7][8][9], c-Myc [10][11][12][13], c-Jun [14][15][16], Mcl-1 [17][18][19], and Notch-1 [20,21] for ubiquitination-mediated destruction. Consistent with the notion that FBW7 exerts its anti-tumor activity in various human malignancies, FBW7 mutation and/or deletion are frequently identified in a variety of human neoplasms [22]; for example, FBW7 mutation rate in T-cell acute lymphoblastic leukemia is approximately 30% [22].…”

“…Recently, multiple new targets of FBW7 including MED13 (Mediator 13), KLF2 (Krüppel-like factor 2), NF-κB2 [47,48], and G-CSFR (Granulocyte colony stimulating factor receptor) [49] have been also discovered. Since several excellent review articles have already summarized the roles of FBW7 in human cancers [20,22,50, 51], we will briefly discuss these newly identified FBW7 substrates that would help us to further understand the critical role of FBW7 in tumorigenesis.…”

PP2ACdc55regulates G1cyclin stability

“…57,58 Evidence points to SCF Fbw8 and SCF Fbx4-α/B-crystallin regulating cyclin D1 stability, 59,60 while cyclin E stability depends on SCF Fbw7 and the BCR (BTB-cul3-Rbx1) ubiquitin ligase complexes. 58,61 Cyclins D1 and E are highly stable in a number of cancers, a phenotype that is thought to aid in cell cycle proliferation and manifestation of the cancer phenotype. 1 In some cases, increased stability is associated with F-box gene mutations and deregulation of ubiquitin ligase activity.…”