FBXL2

FBXL2
Identifiers
Aliases	FBXL2 , FBL2, FBL3, F-box and leucine-rich repeat protein 2, F-box and leucine rich repeat protein 2
External IDs	OMIM: 605652 MGI: 1919429 HomoloGene: 135814 GeneCards: FBXL2
Gene location (Mouse) Chr. Chromosome 9 (mouse) [1] Band 9|9 F3 Start 113,792,705 bp [1] End 113,875,259 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) n/a Top expressed in superior frontal gyrus oocyte secondary oocyte hippocampus proper ventral tegmental area primary motor cortex dorsomedial hypothalamic nucleus dorsal tegmental nucleus cerebellar cortex neural tube BioGPS More reference expression data
Gene ontology Molecular function phosphatidylinositol 3-kinase regulatory subunit binding protein phosphatase binding protein binding calmodulin binding ubiquitin-protein transferase activity Cellular component cytoplasm SCF ubiquitin ligase complex membrane Biological process SCF-dependent proteasomal ubiquitin-dependent protein catabolic process regulation of autophagy viral process protein monoubiquitination protein ubiquitination ubiquitin-dependent protein catabolic process proteolysis regulation of phosphatidylinositol 3-kinase signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 25827 72179 Ensembl ENSG00000153558 ENSMUSG00000032507 UniProt Q9UKC9 Q8BH16 RefSeq (mRNA) NM_001171713 NM_012157 NM_178624 RefSeq (protein) NP_036289 NP_001336245 NP_001336248 NP_001336249 NP_001336250 NP_001336251 NP_001336252 NP_001336253 NP_001336254 NP_001336255 NP_848739 Location (UCSC) n/a Chr 9: 113.79 – 113.88 Mb PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

F-box/LRR-repeat protein 2 is a protein that in humans is encoded by the FBXL2 gene. ^{[4] [5] [6]}

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains 12 tandem leucine-rich repeats. ^[6]

FBXL2 is a highly conserved F-box protein that directly binds substrates and, thus, determines the specificity of the SCF ubiquitin ligase complex. FBXL2 contains a typical CaaX motif that is post-translationally modified by geranyl-geranylation for targeting to cellular membranes. ^{[7] [8] [9]} The importance of the ubiquitin ligase activity of FBXL2 was originally shown in an unbiased screen for cellular host factors necessary for Hepatitis C virus replication. ^[7] Geranyl-geranylation of FBXL2 is essential also for its pro-survival function in mediating poly-ubiquitylation and proteasomal degradation of IP3R3 (a calcium channel at the endoplasmic reticulum) ^[9] and p85β (the regulatory subunit of PI3-Kinases). ^[8]

PI3Ks are heterodimeric lipid kinases composed of a p110 catalytic subunit and a p85 regulatory subunit. FBXL2 interacts with the pool of p85β that is free of p110 subunits to promote p85β, but not p85α, degradation. ^[8] The degradation of p85β via FBXL2 maintains the balance between p85β monomers and p110-p85 heterodimers for efficient activation of PI3K in response to mitogens.

In response to IP3 (inositol 1,4,5-trisphosphate) production, calcium (Ca²⁺) flux between the endoplasmic reticulum and mitochondria is carried out by IP3 receptors (IP3Rs). This event is critical for cellular bioenergetics. The duration and the extent of Ca²⁺ release from IP3Rs determine whether cells survive or die: basal levels of Ca²⁺ release and uptake by the mitochondria is necessary for oxidative phosphorylation and ATP production. However, excessive and/or persistent Ca²⁺ flux results in mitochondrial Ca²⁺ overload and apoptosis. FBXL2 targets IP3R3 for degradation to avoid an excessive and prolonged flux of Ca²⁺ and to attenuate apoptosis in response to stress. ^[9] This process requires presence of FBXL2 at membranes via geranylgeranylation, and is sensitive to GGTi-2418 (a CaaX peptidomimetic geranylgeranylation inhibitor that reached clinical trials). The degradation of IP3R3 is antagonized by the tumor suppressor PTEN, which competes with FBXL2 for binding to IP3R3, thereby preventing IP3R3 degradation and promoting cell death. FBXL2 is geranylgeranylated by GGTase3, a fourth and novel member of the human family of prenyltransferases, identified by the Pagano laboratory. ^[10]

References

1. GRCm38: Ensembl release 89: ENSMUSG00000032507 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Ilyin GP, Rialland M, Glaise D, Guguen-Guillouzo C (October 1999). "Identification of a novel Skp2-like mammalian protein containing F-box and leucine-rich repeats". FEBS Letters. 459 (1): 75–9. doi: 10.1016/S0014-5793(99)01211-9 . PMID   10508920. S2CID   22945082.
5. Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (October 1999). "Identification of a family of human F-box proteins". Current Biology. 9 (20): 1177–9. doi: 10.1016/S0960-9822(00)80020-2 . PMID   10531035. S2CID   7467493.
6. "Entrez Gene: FBXL2 F-box and leucine-rich repeat protein 2".
7. Wang C, Gale M, Keller BC, Huang H, Brown MS, Goldstein JL, Ye J (May 2005). "Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication". Molecular Cell. 18 (4): 425–34. doi: 10.1016/j.molcel.2005.04.004 . PMID   15893726.
8. Kuchay S, Duan S, Schenkein E, Peschiaroli A, Saraf A, Florens L, et al. (May 2013). "FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade". Nature Cell Biology. 15 (5): 472–80. doi:10.1038/ncb2731. PMC   3865866 . PMID   23604317.
9. Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A, et al. (June 2017). "2+-mediated apoptosis limiting tumour growth". Nature. 546 (7659): 554–558. doi:10.1038/nature22965. PMC   5627969 . PMID   28614300.
10. Kuchay et al. GGTase3 is a Newly Identified Geranylgeranyltransferase Targeting a Ubiquitin Ligase.  Nature Str & Mol Biol 26:628-636, 2019.

Further reading

• Ye J (August 2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus". PLOS Pathogens. 3 (8): e108. doi: 10.1371/journal.ppat.0030108 . PMC   1959368 . PMID   17784784.
• Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW (October 1999). "A family of mammalian F-box proteins". Current Biology. 9 (20): 1180–2. doi: 10.1016/S0960-9822(00)80021-4 . PMID   10531037. S2CID   14341845.
• Ilyin GP, Rialland M, Pigeon C, Guguen-Guillouzo C (July 2000). "cDNA cloning and expression analysis of new members of the mammalian F-box protein family". Genomics. 67 (1): 40–7. doi:10.1006/geno.2000.6211. PMID   10945468.
• Wang C, Gale M, Keller BC, Huang H, Brown MS, Goldstein JL, Ye J (May 2005). "Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication". Molecular Cell. 18 (4): 425–34. doi: 10.1016/j.molcel.2005.04.004 . PMID   15893726.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.