# FBXO2

## Overview
FBXO2 is a gene that encodes the F-box protein 2, a member of the F-box protein family, which is characterized by the presence of an F-box motif. This motif is integral to the formation of SCF (SKP1-CUL1-F-box protein) complexes, which are crucial for ubiquitin-mediated proteolysis (Zhao2020FBXO2). F-box protein 2 is categorized as an E3 ubiquitin ligase, playing a pivotal role in the endoplasmic reticulum-associated degradation (ERAD) pathway by targeting glycosylated proteins for ubiquitination and subsequent degradation (Ji2022FBXO2). The protein is particularly significant in neuronal cells, where it helps maintain protein homeostasis and is implicated in various physiological and pathological processes, including neurodegenerative diseases and cancer (Randle2016Fbox; Ji2022FBXO2). The gene's expression and the protein's interactions with specific substrates underscore its importance in cellular regulation and its potential as a therapeutic target in disease contexts (Zhao2020FBXO2; Sun2018FBXO2).

## Structure
FBXO2, also known as F-box protein 2, is a member of the F-box protein family, characterized by the presence of an F-box motif, which is approximately 40 amino acids in length. This motif is crucial for protein-protein interactions, particularly in forming SCF (SKP1-CUL1-F-box protein) complexes that are essential for ubiquitin-mediated proteolysis (Zhao2020FBXO2). The molecular structure of FBXO2 includes several distinct domains: the F-box domain, a PEST domain, and a substrate-binding domain (SBD) (Zhang2018EpsteinBarr). The F-box domain is located at the N-terminus, while the FBA (F-box associated) domain is situated at the C-terminus and is essential for recognizing glycoproteins (Che2020FBXO2).

The FBA domain is critical for the protein's function, as mutations in this domain, such as Tyr278A and Trp279A, abolish its glycoprotein-recognizing ability (Che2020FBXO2). FBXO2 specifically recognizes high-mannose glycoproteins, which are incomplete products of the N-glycosylation pathway (Zhang2018EpsteinBarr). The protein is involved in the ER-associated degradation (ERAD) pathway, where it targets glycosylated proteins for ubiquitination and degradation (Ji2022FBXO2). Post-translational modifications, such as phosphorylation, may regulate its activity, and splice variants could lead to different isoforms with distinct functions (Zhao2020FBXO2).

## Function
FBXO2 (F-box protein 2) is a component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which is crucial for protein degradation via the ubiquitin-proteasome system. This protein is involved in recognizing and binding specific substrates for ubiquitination, thereby regulating protein turnover. FBXO2 is particularly active in the endoplasmic reticulum, where it plays a significant role in maintaining protein homeostasis, especially in neuronal cells (Randle2016Fbox).

In healthy human cells, FBXO2 is originally described as a brain-specific protein and is also found in cochlear cells. Its expression is associated with the regulation of glycoprotein quality, as it recognizes high-mannose glycoproteins through its FBA domain (Zhang2018EpsteinBarr; Song2019Emerging). Knockout studies in mice have shown that the absence of FBXO2 can lead to age-related hearing loss, indicating its importance in auditory function (Zhang2018EpsteinBarr).

FBXO2's role in protein homeostasis is further highlighted by its involvement in targeting glycosylated proteins for degradation, which is essential for cellular processes and maintaining the balance of protein synthesis and degradation in specific tissues (Randle2016Fbox).

## Clinical Significance
FBXO2 has been implicated in various cancers and neurodegenerative diseases due to its role in protein degradation. In glioblastoma, FBXO2 is highly upregulated in recurrent tumors, correlating with poorer survival outcomes. Knockout studies in glioma models have shown increased survival and reduced tumor growth, suggesting a protumorigenic role for FBXO2 in glioblastoma (Buehler2022Quantitative).

In gastric cancer, high FBXO2 expression is associated with lymph node metastasis and shorter overall survival. It promotes proliferation and migration of cancer cells, and its knockdown reduces these activities, indicating its potential as a therapeutic target (Sun2018FBXO2).

FBXO2 also plays a role in ovarian cancer by targeting the glycosylated form of the tumor suppressor protein SUN2 for degradation, which prevents apoptosis and promotes cell proliferation. This process is regulated by the transcription factor SOX6, forming a SOX6-FBXO2-SUN2 axis that contributes to cancer progression (Ji2022FBXO2).

In osteosarcoma, FBXO2 interacts with the STAT3 signaling pathway, enhancing tumorigenicity. Its overexpression increases proliferation, while knockout inhibits these processes, highlighting its oncogenic potential (Zhao2020FBXO2).

FBXO2 is also involved in neurodegenerative conditions, such as Niemann-Pick type C disease, where its deficiency exacerbates the disease phenotype by impairing lysosomal clearance (Liu2020Fbxo2).

## Interactions
FBXO2, a member of the F-box protein family, is involved in various protein interactions, primarily through its role as an E3 ubiquitin ligase. It interacts with glycoproteins that possess high-mannose glycans, facilitating their degradation via the ER-associated degradation (ERAD) pathway. This interaction is crucial for maintaining glycoprotein homeostasis in neurons and is implicated in Alzheimer's disease pathogenesis by regulating amyloid precursor protein (APP) levels and processing (Atkin2014Fbox).

FBXO2 also interacts with the Epstein-Barr virus (EBV) glycoprotein B (gB), targeting it for ubiquitination and degradation. This interaction limits EBV infectivity by reducing gB levels on the plasma membrane, thereby decreasing viral entry and cell fusion (Zhang2018EpsteinBarr).

In cancer biology, FBXO2 interacts with glycosylated SUN2 in ovarian cancer cells, targeting it for ubiquitination and degradation, which may promote cancer progression (Ji2022FBXO2). In osteosarcoma cells, FBXO2 interacts with the interleukin 6 receptor (IL-6R), specifically stabilizing the IL6ST component, which enhances IL-6-induced STAT3 activation, contributing to tumorigenicity (Zhao2020FBXO2).


## References


[1. (Ji2022FBXO2) Jing Ji, Jing Shen, Yuxin Xu, Mengru Xie, Qilan Qian, Teng Qiu, Wen Shi, Dexu Ren, Jinming Ma, Wei Liu, and Bin Liu. Fbxo2 targets glycosylated sun2 for ubiquitination and degradation to promote ovarian cancer development. Cell Death & Disease, May 2022. URL: http://dx.doi.org/10.1038/s41419-022-04892-9, doi:10.1038/s41419-022-04892-9. This article has 15 citations.](https://doi.org/10.1038/s41419-022-04892-9)

[2. (Randle2016Fbox) Suzanne J. Randle and Heike Laman. F-box protein interactions with the hallmark pathways in cancer. Seminars in Cancer Biology, 36:3–17, February 2016. URL: http://dx.doi.org/10.1016/j.semcancer.2015.09.013, doi:10.1016/j.semcancer.2015.09.013. This article has 64 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.semcancer.2015.09.013)

[3. (Zhao2020FBXO2) Xunming Zhao, Weichun Guo, Lixue Zou, and Biao Hu. Fbxo2 modulates stat3 signaling to regulate proliferation and tumorigenicity of osteosarcoma cells. Cancer Cell International, June 2020. URL: http://dx.doi.org/10.1186/s12935-020-01326-4, doi:10.1186/s12935-020-01326-4. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12935-020-01326-4)

[4. (Liu2020Fbxo2) Elaine A. Liu, Mark L. Schultz, Chisaki Mochida, Chan Chung, Henry L. Paulson, and Andrew P. Lieberman. Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the niemann-pick c brain. JCI Insight, October 2020. URL: http://dx.doi.org/10.1172/jci.insight.136676, doi:10.1172/jci.insight.136676. This article has 27 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1172/jci.insight.136676)

[5. (Che2020FBXO2) Xiaoxia Che, Fangfang Jian, Ying Wang, Jingjing Zhang, Jian Shen, Qi Cheng, Xi Wang, Nan Jia, and Weiwei Feng. Fbxo2 promotes proliferation of endometrial cancer by ubiquitin-mediated degradation of fbn1 in the regulation of the cell cycle and the autophagy pathway. Frontiers in Cell and Developmental Biology, August 2020. URL: http://dx.doi.org/10.3389/fcell.2020.00843, doi:10.3389/fcell.2020.00843. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2020.00843)

[6. (Atkin2014Fbox) Graham Atkin, Jack Hunt, Eiko Minakawa, Lisa Sharkey, Nathan Tipper, William Tennant, and Henry L. Paulson. F-box only protein 2 (fbxo2) regulates amyloid precursor protein levels and processing. Journal of Biological Chemistry, 289(10):7038–7048, March 2014. URL: http://dx.doi.org/10.1074/jbc.m113.515056, doi:10.1074/jbc.m113.515056. This article has 32 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m113.515056)

[7. (Sun2018FBXO2) Xu Sun, Teng Wang, Zhang-Rui Guan, Chun Zhang, Yun Chen, Jian Jin, and Dong Hua. Fbxo2, a novel marker for metastasis in human gastric cancer. Biochemical and Biophysical Research Communications, 495(3):2158–2164, January 2018. URL: http://dx.doi.org/10.1016/j.bbrc.2017.12.097, doi:10.1016/j.bbrc.2017.12.097. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2017.12.097)

[8. (Zhang2018EpsteinBarr) Hao-Jiong Zhang, Jinxiu Tian, Xue-Kang Qi, Tong Xiang, Gui-Ping He, Hua Zhang, Xibao Yu, Xiao Zhang, Bingchun Zhao, Qi-Sheng Feng, Ming-Yuan Chen, Mu-Sheng Zeng, Yi-Xin Zeng, and Lin Feng. Epstein-barr virus activates f-box protein fbxo2 to limit viral infectivity by targeting glycoprotein b for degradation. PLOS Pathogens, 14(7):e1007208, July 2018. URL: http://dx.doi.org/10.1371/journal.ppat.1007208, doi:10.1371/journal.ppat.1007208. This article has 25 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1371/journal.ppat.1007208)

[9. (Buehler2022Quantitative) Marcel Buehler, Xiao Yi, Weigang Ge, Peter Blattmann, Elisabeth Rushing, Guido Reifenberger, Joerg Felsberg, Charles Yeh, Jacob E Corn, Luca Regli, Junyi Zhang, Ann Cloos, Vidhya M Ravi, Benedikt Wiestler, Dieter Henrik Heiland, Ruedi Aebersold, Michael Weller, Tiannan Guo, and Tobias Weiss. Quantitative proteomic landscapes of primary and recurrent glioblastoma reveal a protumorigeneic role for fbxo2-dependent glioma-microenvironment interactions. Neuro-Oncology, 25(2):290–302, July 2022. URL: http://dx.doi.org/10.1093/neuonc/noac169, doi:10.1093/neuonc/noac169. This article has 10 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/neuonc/noac169)

[10. (Song2019Emerging) Yizuo Song, Min Lin, Yi Liu, Zhi-Wei Wang, and Xueqiong Zhu. Emerging role of f-box proteins in the regulation of epithelial-mesenchymal transition and stem cells in human cancers. Stem Cell Research & Therapy, April 2019. URL: http://dx.doi.org/10.1186/s13287-019-1222-0, doi:10.1186/s13287-019-1222-0. This article has 33 citations.](https://doi.org/10.1186/s13287-019-1222-0)