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Review
. 2020 Mar 4;10(9):4150-4167.
doi: 10.7150/thno.42735. eCollection 2020.

F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects

Dinesh Singh Tekcham  1 , Di Chen  1 , Yu Liu  2   1 , Ting Ling  1 , Yi Zhang  2   1 , Huan Chen  1 , Wen Wang  1 , Wuxiyar Otkur  1 , Huan Qi  1 , Tian Xia  1 , Xiaolong Liu  1 , Hai-Long Piao  1 , Hongxu Liu  2
Affiliations
Review

F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects

Dinesh Singh Tekcham et al. Theranostics. .

Abstract

E3 ubiquitin ligases play a critical role in cellular mechanisms and cancer progression. F-box protein is the core component of the SKP1-cullin 1-F-box (SCF)-type E3 ubiquitin ligase and directly binds to substrates by various specific domains. According to the specific domains, F-box proteins are further classified into three sub-families: 1) F-box with leucine rich amino acid repeats (FBXL); 2) F-box with WD 40 amino acid repeats (FBXW); 3) F-box only with uncharacterized domains (FBXO). Here, we summarize the substrates of F-box proteins, discuss the important molecular mechanism and emerging role of F-box proteins especially from the perspective of cancer development and progression. These findings will shed new light on malignant tumor progression mechanisms, and suggest the potential role of F-box proteins as cancer biomarkers and therapeutic targets for future cancer treatment.

Keywords: E3 ligase; F-box; cancer progression; substrate; ubiquitin.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
A SCF complex. This complex comprises of scaffold CUL1, SKP1, RBX1/2 and F-box receptor. The substrate is phosphorylated by specific kinase enzyme and recognized by the substrate recognition domain. Ubi is transferred from E2 to E3 ligase/F-box proteins in coordination with RBX1/2 for proteosomal degradation. B Different forms of ubiquitination. After the substrate is presented to F-box protein, different types of ubiquitination occur depending on the number and types of Ubi/Ubis presented to substrates, namely mono-ubiquitination (i.e., single ubiquitin is added to substrate), linear poly Ubi-K63/K48/K11 (many Ubis are added one after another along a line format at lysine K63/K48/K11 locus of Ubis) and multi-poly-Ubi-K63 (Ubis are added in multilayers at lysine K63/K48/K11 locus). Some other Ubi-types are yet undetermined, such as K6, K27, K29, K33, etc. Ubi-K48/K11 types are proteolytic whereas Ubi-K63 and mono-Ubi are non-proteolytic in nature. The substrate is mainly processed at the 26S proteasome complex for ubiquitination guided proteasomal degradation.
Figure 2
Figure 2
Substrates of SKP2 and FBXL2 in various cancer relevant cellular functions and pathways. K63-linkage poly-ubiquitinations are annotated on the arrows, the others are K48-linkage ubiquitinations.
Figure 3
Figure 3
Substrates of FBXL5 in iron homeostasis and various cancer relevant cellular functions and pathways.
Figure 4
Figure 4
Substrates of FBXW family proteins β-TrCP and FBXW7 in various cancer relevant cellular functions and pathways.
Figure 5
Figure 5
Substrates of FBXO family proteins FBXO1, FBXO3 and FBXO4 in various cancer relevant cellular functions and pathways.
See this image and copyright information in PMC

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