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{{Infobox_gene}}
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'''F-box/WD repeat-containing protein 1A''' (FBXW1A) also known as '''βTrCP1''' or '''Fbxw1''' or '''hsSlimb''' or '''pIkappaBalpha-E3 receptor subunit''' is a [[protein]] that in humans is encoded by the ''BTRC'' (beta-transducin repeat containing) [[gene]].<ref name="pmid10331953">{{cite journal |vauthors=Fujiwara T, Suzuki M, Tanigami A, Ikenoue T, Omata M, Chiba T, Tanaka K | title = The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25 | journal = Genomics | volume = 58 | issue = 1 | pages = 104–105 |date=Jul 1999 | pmid = 10331953 | pmc =  | doi = 10.1006/geno.1999.5792 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: BTRC beta-transducin repeat containing| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8945| accessdate = }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
This gene encodes a member of the [[F-box protein]] family which is characterized by an approximately 40 residue [[structural motif]], the F-box. The F-box proteins constitute one of the four subunits of [[ubiquitin]] protein [[ligase]] complex called SCFs ([[Skp1-Cul1-F-box protein]]), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes:
{{GNF_Protein_box
| image = PBB_Protein_BTRC_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1p22.
| PDB = {{PDB2|1p22}}
| Name = Beta-transducin repeat containing
| HGNCid = 1144
| Symbol = BTRC
| AltSymbols =; BETA-TRCP; FBW1A; FBXW1A; FWD1; MGC4643; bTrCP; bTrCP1; betaTrCP
| OMIM = 603482
| ECnumber = 
| Homologene = 39330
| MGIid = 1338871
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0016874 |text = ligase activity}}
| Component = {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}}
| Process = {{GNF_GO|id=GO:0006511 |text = ubiquitin-dependent protein catabolic process}} {{GNF_GO|id=GO:0006512 |text = ubiquitin cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0016055 |text = Wnt receptor signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 8945
    | Hs_Ensembl = ENSG00000166167
    | Hs_RefseqProtein = NP_003930
    | Hs_RefseqmRNA = NM_003939
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 103103810
    | Hs_GenLoc_end = 103307068
    | Hs_Uniprot = Q9Y297
    | Mm_EntrezGene = 12234
    | Mm_Ensembl = ENSMUSG00000025217
    | Mm_RefseqmRNA = NM_001037758
    | Mm_RefseqProtein = NP_001032847
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 45417062
    | Mm_GenLoc_end = 45583324
    | Mm_Uniprot = 
  }}
}}
'''Beta-transducin repeat containing''', also known as '''BTRC''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: BTRC beta-transducin repeat containing| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8945| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
* '''Fbxws''' containing [[WD40 repeat]]s,
{{PBB_Summary
* '''Fbxls''' containing [[leucine-rich repeat]]s,
| section_title =  
* and '''Fbxos''' containing either "other" protein–protein interaction modules or no recognizable motifs.
| summary_text = 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 Fbws class; in addition to an F-box, this protein contains multiple WD-40 repeats. This protein is homologous to Xenopus bTrCP1, yeast Met30, Neurospora Scon2 and Drosophila Slimb proteins. It interacts with HIV-1 Vpu and connects CD4 to the proteolytic machinery. It also associates specifically with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by activating the NF-kappaB pathway and inhibiting the beta-catenin pathway.<ref name="entrez">{{cite web | title = Entrez Gene: BTRC beta-transducin repeat containing| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8945| accessdate = }}</ref>
 
}}
The protein encoded by this gene belongs to the '''Fbxw''' class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to [[Xenopus]] βTrCP, [[yeast]] [[Met30]], [[Neurospora]] [[Scon2]] and [[Drosophila]] [[Slimb]]. In mammals, in addition to βTrCP1, a paralog protein (called βTrCP2 or [[FBXW11]]) also exists, but, so far, their functions appear redundant and indistinguishable.
 
== Discovery ==
Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the [[HIV-1]] [[Vpu]] viral protein to eliminate cellular [[CD4]] by connecting it to the proteolytic machinery.<ref name="Margottin, F. et al.">{{cite journal |vauthors=Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R | title = A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif | journal = Mol Cell | volume = 1 | issue = 4 | pages = 565–574 |date=Jul 1998 | pmid = 9660940 | pmc = | doi =10.1016/S1097-2765(00)80056-8  }}</ref> Subsequently, βTrCP was shown to regulate multiple cellular processes  by mediating the degradation of various targets.<ref name="Frescas, D. & Pagano, M.">{{Cite journal
| last1 = Frescas | first1 = D.
| last2 = Pagano | first2 = M.
| title = Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: Tipping the scales of cancer
| doi = 10.1038/nrc2396
| journal = Nature Reviews Cancer
| volume = 8
| issue = 6
| pages = 438–449
| year = 2008
| pmc = 2711846
| pmid = 18500245
}}</ref> Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A,<ref name="Busino, L. et al.">{{Cite journal
| last1 = Busino | first1 = L.
| last2 = Donzelli | first2 = M.
| last3 = Chiesa | first3 = M.
| last4 = Guardavaccaro | first4 = D.
| last5 = Ganoth | first5 = D.
| last6 = Dorrello | first6 = N.
| last7 = Hershko | first7 = A.
| last8 = Pagano | first8 = M.
| last9 = Draetta | first9 = G. F.
| doi = 10.1038/nature02082
| title = Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage
| journal = Nature
| volume = 426
| issue = 6962
| pages = 87–91
| year = 2003
| pmid = 14603323
}}</ref> whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation.<ref name="Watanabe, N. et al.">{{Cite journal
| last1 = Watanabe | first1 = N.
| last2 = Arai | first2 = H.
| last3 = Nishihara | first3 = Y.
| last4 = Taniguchi | first4 = M.
| last5 = Watanabe | first5 = N.
| last6 = Hunter | first6 = T.
| last7 = Osada | first7 = H.
| doi = 10.1073/pnas.0307700101
| title = M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP
| journal = Proceedings of the National Academy of Sciences
| volume = 101
| issue = 13
| pages = 4419–4424
| pmc = 384762
| year = 2004
| pmid = 15070733
}}</ref> In early mitosis, βTrCP mediates the degradation of EMI1,<ref name="Guardavaccaro, D. et al.">{{Cite journal
| doi = 10.1016/S1534-5807(03)00154-0
| last1 = Guardavaccaro | first1 = D.
| last2 = Kudo | first2 = Y.
| last3 = Boulaire | first3 = J.
| last4 = Barchi | first4 = M.
| last5 = Busino | first5 = L.
| last6 = Donzelli | first6 = M.
| last7 = Margottin-Goguet | first7 = F.
| last8 = Jackson | first8 = P. K.
| last9 = Yamasaki | first9 = L.
| last10 = Pagano | first10 = M.
| title = Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo
| journal = Developmental Cell
| volume = 4
| issue = 6
| pages = 799–812
| year = 2003
| pmid = 12791266
}}</ref><ref name="Margottin-Goguet, F. et al.">{{Cite journal
| last1 = Margottin-Goguet | first1 = F.
| last2 = Hsu | first2 = J. Y.
| last3 = Loktev | first3 = A.
| last4 = Hsieh | first4 = H. M.
| last5 = Reimann | first5 = J. D.
| last6 = Jackson | first6 = P. K.
| title = Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase
| journal = Developmental Cell
| volume = 4
| issue = 6
| pages = 813–826
| year = 2003
| pmid = 12791267 | doi=10.1016/S1534-5807(03)00153-9
}}</ref> an inhibitor of the [[APC/C]] ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.<ref name="Guardavaccaro, D., Frescas, D. et al.">{{Cite journal
| last1 = Guardavaccaro | first1 = D.
| last2 = Frescas | first2 = D.
| last3 = Dorrello | first3 = N. V.
| last4 = Peschiaroli | first4 = A.
| last5 = Multani | first5 = A. S.
| last6 = Cardozo | first6 = T.
| last7 = Lasorella | first7 = A.
| last8 = Iavarone | first8 = A.
| last9 = Chang | first9 = S.
| last10 = Hernando | first10 = E.
| last11 = Pagano | first11 = M.
| title = Control of chromosome stability by the β-TrCP–REST–Mad2 axis
| doi = 10.1038/nature06641
| journal = Nature
| volume = 452
| issue = 7185
| pages = 365–369
| pmc = 2707768
| year = 2008
| pmid = 18354482
}}</ref>
 
== Function ==
βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1,<ref name="Busino, L. et al." /><ref name="Jin, J. et al.">{{Cite journal
| last1 = Jin | first1 = J.
| last2 = Shirogane | first2 = T.
| last3 = Xu | first3 = L.
| last4 = Nalepa | first4 = G.
| last5 = Qin | first5 = J.
| last6 = Elledge | first6 = S. J.
| last7 = Harper | first7 = J. W.
| title = SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase
| doi = 10.1101/gad.1157503
| journal = Genes & Development
| volume = 17
| issue = 24
| pages = 3062–3074
| year = 2003
| pmid = 14681206
| pmc =305258
}}</ref> thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner.<ref name="Peschiaroli, A. et al.">{{Cite journal
| last1 = Peschiaroli | first1 = A.
| last2 = Dorrello | first2 = N. V.
| last3 = Guardavaccaro | first3 = D.
| last4 = Venere | first4 = M.
| last5 = Halazonetis | first5 = T.
| last6 = Sherman | first6 = N. E.
| last7 = Pagano | first7 = M.
| doi = 10.1016/j.molcel.2006.06.013
| title = SCFβTrCP-Mediated Degradation of Claspin Regulates Recovery from the DNA Replication Checkpoint Response
| journal = Molecular Cell
| volume = 23
| issue = 3  
| pages = 319–329
| year = 2006
| pmid = 16885022
| pmc =
}}</ref><ref name=" Mailand, N., Bekker-Jensen, S., Bartek, J. & Lukas, J.">{{Cite journal
| last1 = Mailand | first1 = N.
| last2 = Bekker-Jensen | first2 = S.
| last3 = Bartek | first3 = J.
| last4 = Lukas | first4 = J.
| title = Destruction of Claspin by SCFβTrCP Restrains Chk1 Activation and Facilitates Recovery from Genotoxic Stress
| doi = 10.1016/j.molcel.2006.06.016
| journal = Molecular Cell
| volume = 23
| issue = 3
| pages = 307–318
| year = 2006
| pmid = 16885021
| pmc =
}}</ref><ref name="Mamely, I. et al.">{{Cite journal
| last1 = Mamely | first1 = I.
| last2 = Van Vugt | first2 = M. A. M.
| last3 = Smits | first3 = V. A.
| last4 = Semple | first4 = J. I.
| last5 = Lemmens | first5 = B.
| last6 = Perrakis | first6 = A.
| last7 = Medema | first7 = R. H.
| last8 = Freire | first8 = R.
| doi = 10.1016/j.cub.2006.08.026
| title = Polo-like Kinase-1 Controls Proteasome-Dependent Degradation of Claspin during Checkpoint Recovery
| journal = Current Biology
| volume = 16
| issue = 19
| pages = 1950–1955
| year = 2006
| pmid = 16934469
| pmc =
}}</ref>
 
βTrCP has also emerged as an important player in protein translation, cell grow and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth.<ref name="Dorrello, N.V. et al.">{{Cite journal
| last1 = Dorrello | first1 = N. V.
| last2 = Peschiaroli | first2 = A.
| last3 = Guardavaccaro | first3 = D.
| last4 = Colburn | first4 = N. H.
| last5 = Sherman | first5 = N. E.
| last6 = Pagano | first6 = M.
| doi = 10.1126/science.1130276
| title = S6K1- and  TRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth
| journal = Science
| volume = 314
| issue = 5798
| pages = 467–471
| year = 2006
| pmid = 17053147
| pmc =
}}</ref> βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR.<ref name="Duan, S. et al.">{{Cite journal
| last1 = Duan | first1 = S.
| last2 = Skaar | first2 = J. R.
| last3 = Kuchay | first3 = S.
| last4 = Toschi | first4 = A.
| last5 = Kanarek | first5 = N.
| last6 = Ben-Neriah | first6 = Y.
| last7 = Pagano | first7 = M.
| doi = 10.1016/j.molcel.2011.09.005
| title = MTOR Generates an Auto-Amplification Loop by Triggering the βTrCP- and CK1α-Dependent Degradation of DEPTOR
| journal = Molecular Cell
| volume = 44
| issue = 2
| pages = 317–324
| year = 2011
| pmid = 22017877
| pmc = 3212871
}}</ref><ref name="Zhao, Y., Xiong, X. & Sun, Y.">{{Cite journal
| last1 = Zhao | first1 = Y.
| last2 = Xiong | first2 = X.
| last3 = Sun | first3 = Y.
| doi = 10.1016/j.molcel.2011.08.029
| title = DEPTOR, an mTOR Inhibitor, is a Physiological Substrate of SCFβTrCP E3 Ubiquitin Ligase and Regulates Survival and Autophagy
| journal = Molecular Cell
| volume = 44
| issue = 2
| pages = 304–316
| year = 2011
| pmid = 22017876
| pmc = 3216641
}}</ref><ref name="Gao, D. et al.">{{Cite journal
| last1 = Gao | first1 = D.
| last2 = Inuzuka | first2 = H.
| last3 = Tan | first3 = M. K. M.
| last4 = Fukushima | first4 = H.
| last5 = Locasale | first5 = J. W.
| last6 = Liu | first6 = P.
| last7 = Wan | first7 = L.
| last8 = Zhai | first8 = B.
| last9 = Chin | first9 = Y.  R.
| last10 = Shaik
| doi = 10.1016/j.molcel.2011.08.030 | first10 = S.
| last11 = Lyssiotis | first11 = C. A.
| last12 = Gygi | first12 = S. P.
| last13 = Toker | first13 = A.
| last14 = Cantley | first14 = L. C.
| last15 = Asara | first15 = J. M.
| last16 = Harper | first16 = J.  W.
| last17 = Wei | first17 = W.  
| title = MTOR Drives Its Own Activation via SCFβTrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR
| journal = Molecular Cell
| volume = 44
| issue = 2
| pages = 290–303
| year = 2011
| pmid = 22017875
| pmc =3229299
}}</ref> At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.<ref name="Dehan, E. et al.">{{Cite journal
| last1 = Dehan | first1 = E.
| last2 = Bassermann | first2 = F.
| last3 = Guardavaccaro | first3 = D.
| last4 = Vasiliver-Shamis | first4 = G.
| last5 = Cohen | first5 = M.
| last6 = Lowes | first6 = K. N.
| last7 = Dustin | first7 = M.
| last8 = Huang | first8 = D. C. S.
| last9 = Taunton | first9 = J.
| doi = 10.1016/j.molcel.2008.12.020
| last10 = Pagano | first10 = M.  
| title = ΒTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis
| journal = Molecular Cell
| volume = 33
| issue = 1
| pages = 109–116
| year = 2009
| pmid = 19150432
| pmc =2655121
}}</ref>
 
βTrCP also associates with phosphorylated [[IkappaBalpha]] and [[beta-catenin]] destruction motifs, probably functioning in multiple transcriptional programs by regulating the [[NF-kappaB]] and the [[WNT pathway]]s.<ref name="Winston, J.T. et al.">{{Cite journal
| last1 = Winston | first1 = J. T.
| last2 = Strack | first2 = P.
| last3 = Beer-Romero | first3 = P.
| last4 = Chu | first4 = C. Y.
| last5 = Elledge | first5 = S. J.
| last6 = Harper | first6 = J. W.
| title = The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro
| journal = Genes & Development
| volume = 13
| issue = 3
| pages = 270–283
| year = 1999
| pmid = 9990852
| pmc = 316433 | doi=10.1101/gad.13.3.270
}}</ref><ref name="Latres, E., Chiaur, D.S. & Pagano, M.">{{Cite journal
| last1 = Latres | first1 = E.
| last2 = Chiaur | first2 = D. S.
| last3 = Pagano | first3 = M.
| doi = 10.1038/sj.onc.1202653
| title = The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin
| journal = Oncogene
| volume = 18
| issue = 4
| pages = 849–854
| year = 1999
| pmid = 10023660
| pmc =
}}</ref>
 
== Interactions ==
BTRC (gene) has been shown to [[Protein–protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[β-catenin]],<ref name="Latres, E., Chiaur, D.S. & Pagano, M."/><ref name=" Liu, C. et al.">{{Cite journal
| last1 = Liu | first1 = C.
| last2 = Kato | first2 = Y.
| last3 = Zhang | first3 = Z.
| last4 = Do | first4 = V. M.
| last5 = Yankner | first5 = B. A.
| last6 = He | first6 = X.
| title = Β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation
| journal = Proceedings of the National Academy of Sciences of the United States of America
| volume = 96
| issue = 11
| pages = 6273–6278
| year = 1999
| pmid = 10339577
| pmc = 26871 | doi=10.1073/pnas.96.11.6273
}}</ref>
* [[BCL2L11|BimEL1]]<ref name="Dehan, E. et al."/>
* [[Cdc25A]],<ref name="Busino, L. et al."/><ref name="Jin, J. et al."/>
* [[CDC34]],<ref name="Cenciarelli, C. et al.">{{Cite journal | last1 = Cenciarelli | first1 = C. | last2 = Chiaur | first2 = D. S. | last3 = Guardavaccaro | first3 = D. | last4 = Parks | first4 = W. | last5 = Vidal | first5 = M. | last6 = Pagano | first6 = M. | doi = 10.1016/S0960-9822(00)80020-2 | title = Identification of a family of human F-box proteins | journal = Current Biology | volume = 9 | issue = 20 | pages = 1177–1179 | year = 1999 | pmid =  10531035| pmc = }}</ref><ref name="pmid12037680">{{cite journal |vauthors=Semplici F, Meggio F, Pinna LA, Oliviero S | title = CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation | journal = Oncogene | volume = 21 | issue = 25 | pages = 3978–87 |date=June 2002 | pmid = 12037680 | doi = 10.1038/sj.onc.1205574 }}</ref>
* [[CLSPN|Claspin]],<ref name="Peschiaroli, A. et al."/><ref name=" Mailand, N., Bekker-Jensen, S., Bartek, J. & Lukas, J."/><ref name="Mamely, I. et al."/>
* [[CUL1]],<ref name="Cenciarelli, C. et al."/><ref name=pmid10644755/><ref name="Min, K.W. et al.">{{Cite journal | last1 = Min | first1 = K. -W. | last2 = Hwang | first2 = J. W. | last3 = Lee | first3 = J. S. | last4 = Park | first4 = Y. | last5 = Tamura | first5 = T. A. | last6 = Yoon | first6 = J. B. | title = TIP120A Associates with Cullins and Modulates Ubiquitin Ligase Activity | doi = 10.1074/jbc.M213070200 | journal = Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15905–15910 | year = 2003 | pmid =  12609982| pmc = }}</ref>
* [[DEPTOR]],<ref name="Duan, S. et al."/><ref name="Zhao, Y., Xiong, X. & Sun, Y."/><ref name="Gao, D. et al."/>
* [[DLG1]],<ref name="pmid12902344">{{cite journal |vauthors=Mantovani F, Banks L | title = Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor | journal = J. Biol. Chem. | volume = 278 | issue = 43 | pages = 42477–86 |date=October 2003 | pmid = 12902344 | doi = 10.1074/jbc.M302799200 }}</ref>
* [[FBXO5|EMI1]],<ref name="Guardavaccaro, D. et al."/><ref name="Margottin-Goguet, F. et al."/>
* [[FBXW11]],<ref name="pmid10644755">{{cite journal |vauthors=Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K | title = Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination | journal = J. Biol. Chem. | volume = 275 | issue = 4 | pages = 2877–84 |date=January 2000 | pmid = 10644755 | doi = 10.1074/jbc.275.4.2877 }}</ref>
* [[IκBα]],<ref name=pmid10644755/><ref name="pmid9990853">{{cite journal |vauthors=Spencer E, Jiang J, Chen ZJ | title = Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP | journal = Genes Dev. | volume = 13 | issue = 3 | pages = 284–94 |date=February 1999 | pmid = 9990853 | pmc = 316434 | doi = 10.1101/gad.13.3.284 }}</ref>
* [[NFKB2]],<ref name="pmid11994270">{{cite journal |vauthors=Fong A, Sun SC | title = Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100 | journal = J. Biol. Chem. | volume = 277 | issue = 25 | pages = 22111–4 |date=June 2002 | pmid = 11994270 | doi = 10.1074/jbc.C200151200 | url = }}</ref><ref name="pmid18617892">{{cite journal |vauthors=Vatsyayan J, Qing G, Xiao G, Hu J | title = SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing | journal = EMBO Rep. | volume = 9 | issue = 9 | pages = 885–90 |date=September 2008 | pmid = 18617892 | pmc = 2529344 | doi = 10.1038/embor.2008.122 }}</ref>
* [[PDCD4]],<ref name="Dorrello, N.V. et al."/>
* [[RELA]],<ref name=pmid9990853/>
* [[REST]],<ref name="Guardavaccaro, D. et al."/><ref name="Westbrook, T.F. et al.">{{Cite journal
| last1 = Westbrook | first1 = T. F.
| last2 = Hu | first2 = G.
| last3 = Ang | first3 = X. L.
| last4 = Mulligan | first4 = P.
| last5 = Pavlova | first5 = N. N.
| last6 = Liang | first6 = A.
| last7 = Leng | first7 = Y.
| last8 = Maehr | first8 = R.
| last9 = Shi | first9 = Y.
| last10 = Harper
| doi = 10.1038/nature06780 | first10 = J. W.
| last11 = Elledge | first11 = S. J.
| title = SCFβTRCPControls Oncogenic Transformation and Neural Differentiation Through REST Degradation
| journal = Nature
| volume = 452
| issue = 7185
| pages = 370–374
| year = 2008
| pmid = 18354483
| pmc =2688689
}}</ref>
* [[SKP1A]],<ref name="Margottin, F. et al." /><ref name="Cenciarelli, C. et al."/><ref name="pmid10644755"/><ref name="Min, K.W. et al."/><ref name="Strack, P. et al.">{{Cite journal | last1 = Strack | first1 = P. | last2 = Caligiuri | first2 = M. | last3 = Pelletier | first3 = M. | last4 = Boisclair | first4 = M. | last5 = Theodoras | first5 = A. | last6 = Beer-Romero | first6 = P. | last7 = Glass | first7 = S. | last8 = Parsons | first8 = T. | last9 = Copeland | first9 = R. A. | last10 = Auger | first10 = K. R. | last11 = Benfield | first11 = P. | last12 = Brizuela | first12 = L. | last13 = Rolfe | first13 = M. | title = SCFβ-TRCP and phosphorylation dependent ubiquitination of IκBα catalyzed by Ubc3 and Ubc4 | journal = Oncogene | volume = 19 | issue = 31 | pages = 3529–3536 | year = 2000 | pmid = 10918611 | doi = 10.1038/sj.onc.1203647}}</ref> and
* [[WEE1]].<ref name="Watanabe, N. et al."/>
{{Div col end}}
*[[C22orf25]]<ref>{{cite web|title=Molecular Interaction Database|url=http://mint.bio.uniroma2.it/mint/Welcome.do}}</ref>
 
==Clinical Significance==
βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal,<ref name="Ougolkov, A. et al.">{{Cite journal | last1 = Ougolkov | first1 = A. | last2 = Zhang | first2 = B. | last3 = Yamashita | first3 = K. | last4 = Bilim | first4 = V. | last5 = Mai | first5 = M. | last6 = Fuchs | first6 = S. Y. | last7 = Minamoto | first7 = T. | doi = 10.1093/jnci/djh219 | title = Associations Among  -TrCP, an E3 Ubiquitin Ligase Receptor,  -Catenin, and NF- B in Colorectal Cancer | journal = JNCI Journal of the National Cancer Institute | volume = 96 | issue = 15 | pages = 1161–1170 | year = 2004 | pmid =  15292388| pmc = }}</ref> pancreatic,<ref name="Muerkoster, S. et al.">{{Cite journal | last1 = Muerkoster | first1 = S. | last2 = Arlt | first2 = A. | last3 = Sipos | first3 = B. | last4 = Witt | first4 = M. | last5 = Grossmann | first5 = M. | last6 = Klöppel | first6 = G. | last7 = Kalthoff | first7 = H. | last8 = Fölsch | first8 = U. R. | last9 = Schäfer | first9 = H. | title = Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit  TRCP1 Relates to Constitutive Nuclear Factor- B Activation and Chemoresistance in Pancreatic Carcinoma Cells | doi = 10.1158/0008-5472.CAN-04-1626 | journal = Cancer Research | volume = 65 | issue = 4 | pages = 1316–1324 | year = 2005 | pmid =  15735017| pmc = }}</ref> hapatoblastoma,<ref name="Koch, A. et al.">{{Cite journal | last1 = Koch | first1 = A. | last2 = Waha | first2 = A. | last3 = Hartmann | first3 = W. | last4 = Hrychyk | first4 = A. | last5 = Schüller | first5 = U. | last6 = Waha | first6 = A. | last7 = Wharton Jr | first7 = K. A. | last8 = Fuchs | first8 = S. Y. | last9 = Von Schweinitz | first9 = D. | last10 = Pietsch | first10 = T. | title = Elevated Expression of Wnt Antagonists is a Common Event in Hepatoblastomas | doi = 10.1158/1078-0432.CCR-04-1162 | journal = Clinical Cancer Research | volume = 11 | issue = 12 | pages = 4295–4304 | year = 2005 | pmid = 15958610| pmc = }}</ref> and breast cancers.<ref name="Spiegelman, V.S. et al.">{{Cite journal | last1 = Spiegelman | first1 = V. S. | last2 = Tang | first2 = W. | last3 = Chan | first3 = A. M. | last4 = Igarashi | first4 = M. | last5 = Aaronson | first5 = S. A. | last6 = Sassoon | first6 = D. A. | last7 = Katoh | first7 = M. | last8 = Slaga | first8 = T. J. | last9 = Fuchs | first9 = S. Y. | title = Induction of Homologue of Slimb Ubiquitin Ligase Receptor by Mitogen Signaling | doi = 10.1074/jbc.M204524200 | journal = Journal of Biological Chemistry | volume = 277 | issue = 39 | pages = 36624–36630 | year = 2002 | pmid =  12151397| pmc = }}</ref>


==References==
==References==
{{reflist|2}}
{{Reflist|colwidth=35em}}
 
==External links==
* {{UCSC gene info|BTRC}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{Refbegin|colwidth=35em}}
{{PBB_Further_reading
*{{cite journal |vauthors=Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ | title = SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation | journal = Nature | volume = 452 | issue = 7185 | pages = 370–374 |date=Mar 2008 | pmid = 18354483 | pmc = 2688689 | doi = 10.1038/nature06780 }}
| citations =
*{{cite journal  | author=Maniatis T |title=A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. |journal=Genes Dev. |volume=13 |issue= 5 |pages= 505–510 |year= 1999 |pmid= 10072378 |doi=10.1101/gad.13.5.505  }}
*{{cite journal | author=Maniatis T |title=A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. |journal=Genes Dev. |volume=13 |issue= 5 |pages= 505-10 |year= 1999 |pmid= 10072378 |doi= }}
*{{cite journal  |vauthors=Li L, Li HS, Pauza CD |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions. |journal=Cell Res. |volume=15 |issue= 11–12 |pages= 923–934 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 |display-authors=etal}}
*{{cite journal  | author=Li L, Li HS, Pauza CD, ''et al.'' |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions. |journal=Cell Res. |volume=15 |issue= 11-12 |pages= 923-34 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 }}
*{{cite journal  |vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 }}
*{{cite journal  | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi= }}
*{{cite journal  |vauthors=Yaron A, Hatzubai A, Davis M |title=Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. |journal=Nature |volume=396 |issue= 6711 |pages= 590–594 |year= 1999 |pmid= 9859996 |doi= 10.1038/25159 |display-authors=etal}}
*{{cite journal  | author=Margottin F, Bour SP, Durand H, ''et al.'' |title=A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. |journal=Mol. Cell |volume=1 |issue= 4 |pages= 565-74 |year= 1998 |pmid= 9660940 |doi=  }}
*{{cite journal  |vauthors=Winston JT, Strack P, Beer-Romero P |title=The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. |journal=Genes Dev. |volume=13 |issue= 3 |pages= 270–283 |year= 1999 |pmid= 9990852 |doi=10.1101/gad.13.3.270  | pmc=316433 |display-authors=etal}}
*{{cite journal  | author=Yaron A, Hatzubai A, Davis M, ''et al.'' |title=Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. |journal=Nature |volume=396 |issue= 6711 |pages= 590-4 |year= 1999 |pmid= 9859996 |doi= 10.1038/25159 }}
*{{cite journal  |vauthors=Spencer E, Jiang J, Chen ZJ |title=Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. |journal=Genes Dev. |volume=13 |issue= 3 |pages= 284–294 |year= 1999 |pmid= 9990853 |doi=10.1101/gad.13.3.284  | pmc=316434  }}
*{{cite journal  | author=Winston JT, Strack P, Beer-Romero P, ''et al.'' |title=The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. |journal=Genes Dev. |volume=13 |issue= 3 |pages= 270-83 |year= 1999 |pmid= 9990852 |doi=  }}
*{{cite journal  |vauthors=Kitagawa M, Hatakeyama S, Shirane M |title=An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. |journal=EMBO J. |volume=18 |issue= 9 |pages= 2401–2410 |year= 1999 |pmid= 10228155 |doi= 10.1093/emboj/18.9.2401 | pmc=1171323 |display-authors=etal}}
*{{cite journal  | author=Spencer E, Jiang J, Chen ZJ |title=Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. |journal=Genes Dev. |volume=13 |issue= 3 |pages= 284-94 |year= 1999 |pmid= 9990853 |doi= }}
*{{cite journal  |vauthors=Wu C, Ghosh S |title=beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. |journal=J. Biol. Chem. |volume=274 |issue= 42 |pages= 29591–4 |year= 1999 |pmid= 10514424 |doi=10.1074/jbc.274.42.29591  }}
*{{cite journal  | author=Kitagawa M, Hatakeyama S, Shirane M, ''et al.'' |title=An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. |journal=EMBO J. |volume=18 |issue= 9 |pages= 2401-10 |year= 1999 |pmid= 10228155 |doi= 10.1093/emboj/18.9.2401 }}
*{{cite journal  |vauthors=Cenciarelli C, Chiaur DS, Guardavaccaro D |title=Identification of a family of human F-box proteins. |journal=Curr. Biol. |volume=9 |issue= 20 |pages= 1177–9 |year= 1999 |pmid= 10531035 |doi= 10.1016/S0960-9822(00)80020-2 |display-authors=etal}}
*{{cite journal  | author=Fujiwara T, Suzuki M, Tanigami A, ''et al.'' |title=The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25. |journal=Genomics |volume=58 |issue= 1 |pages= 104-5 |year= 1999 |pmid= 10331953 |doi= 10.1006/geno.1999.5792 }}
*{{cite journal  |vauthors=Stone DM, Murone M, Luoh S |title=Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. | series=112 |journal=J. Cell Sci. |volume=( Pt 23) |issue= |pages= 4437–4448 |year= 2000 |pmid= 10564661 |doi= |display-authors=etal}}
*{{cite journal  | author=Wu C, Ghosh S |title=beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. |journal=J. Biol. Chem. |volume=274 |issue= 42 |pages= 29591-4 |year= 1999 |pmid= 10514424 |doi= }}
*{{cite journal  |vauthors=Suzuki H, Chiba T, Suzuki T |title=Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. |journal=J. Biol. Chem. |volume=275 |issue= 4 |pages= 2877–2884 |year= 2000 |pmid= 10644755 |doi=10.1074/jbc.275.4.2877 |display-authors=etal}}
*{{cite journal  | author=Cenciarelli C, Chiaur DS, Guardavaccaro D, ''et al.'' |title=Identification of a family of human F-box proteins. |journal=Curr. Biol. |volume=9 |issue= 20 |pages= 1177-9 |year= 1999 |pmid= 10531035 |doi= 10.1016/S0960-9822(00)80020-2 }}
*{{cite journal  |vauthors=Read MA, Brownell JE, Gladysheva TB |title=Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. |journal=Mol. Cell. Biol. |volume=20 |issue= 7 |pages= 2326–2333 |year= 2000 |pmid= 10713156 |doi=10.1128/MCB.20.7.2326-2333.2000  | pmc=85397  |display-authors=etal}}
*{{cite journal  | author=Stone DM, Murone M, Luoh S, ''et al.'' |title=Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. |journal=J. Cell. Sci. |volume=112 ( Pt 23) |issue= |pages= 4437-48 |year= 2000 |pmid= 10564661 |doi=  }}
*{{cite journal  |vauthors=Sadot E, Simcha I, Iwai K |title=Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system. |journal=Oncogene |volume=19 |issue= 16 |pages= 1992–2001 |year= 2000 |pmid= 10803460 |doi= 10.1038/sj.onc.1203519 |display-authors=etal}}
*{{cite journal  | author=Suzuki H, Chiba T, Suzuki T, ''et al.'' |title=Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. |journal=J. Biol. Chem. |volume=275 |issue= 4 |pages= 2877-84 |year= 2000 |pmid= 10644755 |doi= }}
*{{cite journal  |vauthors=Chiaur DS, Murthy S, Cenciarelli C |title=Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors. |journal=Cytogenet. Cell Genet. |volume=88 |issue= 3–4 |pages= 255–258 |year= 2000 |pmid= 10828603 |doi=10.1159/000015532  |display-authors=etal}}
*{{cite journal  | author=Read MA, Brownell JE, Gladysheva TB, ''et al.'' |title=Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. |journal=Mol. Cell. Biol. |volume=20 |issue= 7 |pages= 2326-33 |year= 2000 |pmid= 10713156 |doi= }}
*{{cite journal  |vauthors=Orian A, Gonen H, Bercovich B |title=SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. |journal=EMBO J. |volume=19 |issue= 11 |pages= 2580–2591 |year= 2000 |pmid= 10835356 |doi= 10.1093/emboj/19.11.2580  | pmc=212749 |display-authors=etal}}
*{{cite journal  | author=Sadot E, Simcha I, Iwai K, ''et al.'' |title=Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system. |journal=Oncogene |volume=19 |issue= 16 |pages= 1992-2001 |year= 2000 |pmid= 10803460 |doi= 10.1038/sj.onc.1203519 }}
*{{cite journal  |vauthors=Strack P, Caligiuri M, Pelletier M |title=SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4. |journal=Oncogene |volume=19 |issue= 31 |pages= 3529–3536 |year= 2000 |pmid= 10918611 |doi= 10.1038/sj.onc.1203647 |display-authors=etal}}
*{{cite journal  | author=Chiaur DS, Murthy S, Cenciarelli C, ''et al.'' |title=Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors. |journal=Cytogenet. Cell Genet. |volume=88 |issue= 3-4 |pages= 255-8 |year= 2000 |pmid= 10828603 |doi= }}
*{{cite journal  |vauthors=Kleijnen MF, Shih AH, Zhou P |title=The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. |journal=Mol. Cell |volume=6 |issue= 2 |pages= 409–419 |year= 2000 |pmid= 10983987 |doi=10.1016/S1097-2765(00)00040-X |display-authors=etal}}
*{{cite journal  | author=Orian A, Gonen H, Bercovich B, ''et al.'' |title=SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. |journal=EMBO J. |volume=19 |issue= 11 |pages= 2580-91 |year= 2000 |pmid= 10835356 |doi= 10.1093/emboj/19.11.2580 }}
{{Refend}}
*{{cite journal  | author=Strack P, Caligiuri M, Pelletier M, ''et al.'' |title=SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4. |journal=Oncogene |volume=19 |issue= 31 |pages= 3529-36 |year= 2000 |pmid= 10918611 |doi= 10.1038/sj.onc.1203647 }}
*{{cite journal | author=Kleijnen MF, Shih AH, Zhou P, ''et al.'' |title=The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. |journal=Mol. Cell |volume=6 |issue= 2 |pages= 409-19 |year= 2000 |pmid= 10983987 |doi=  }}
}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=8945}}
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Revision as of 19:24, 8 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC (beta-transducin repeat containing) gene.[1][2]

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 residue structural motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (Skp1-Cul1-F-box protein), which often, but not always, recognize substrates in a phosphorylation-dependent manner. F-box proteins are divided into 3 classes:

  • Fbxws containing WD40 repeats,
  • Fbxls containing leucine-rich repeats,
  • and Fbxos containing either "other" protein–protein interaction modules or no recognizable motifs.

The protein encoded by this gene belongs to the Fbxw class as, in addition to an F-box, this protein contains multiple WD40 repeats. This protein is homologous to Xenopus βTrCP, yeast Met30, Neurospora Scon2 and Drosophila Slimb. In mammals, in addition to βTrCP1, a paralog protein (called βTrCP2 or FBXW11) also exists, but, so far, their functions appear redundant and indistinguishable.

Discovery

Human βTrCP (referred to both βTrCP1 and βTrCP2) was originally identified as a cellular ubiquitin ligase that is bound by the HIV-1 Vpu viral protein to eliminate cellular CD4 by connecting it to the proteolytic machinery.[3] Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets.[4] Cell cycle regulators constitute a major group of βTrCP substrates. During S phase, βTrCP keeps CDK1 in check by promoting the degradation of the phosphatase CDC25A,[5] whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation.[6] In early mitosis, βTrCP mediates the degradation of EMI1,[7][8] an inhibitor of the APC/C ubiquitin ligase complex, which is responsible for the anaphase-metaphase transition (by inducing the proteolysis of Securin) and mitotic exit (by driving the degradation of mitotic CDK1 activating cyclin subunits). Furthermore, βTrCP controls APC/C by targeting REST, thereby removing its transcriptional repression on MAD2, an essential component of the spindle assembly checkpoint that keeps APC/C inactive until all chromatids are attached to the spindle microtubles.[9]

Function

βTrCP plays important roles in regulating cell cycle checkpoints. In response to genotoxic stress, it contributes to turn off CDK1 activity by mediating the degradation of CDC25A in collaboration with Chk1,[5][10] thereby preventing cell cycle progression before the completion of DNA repair. During recovery from DNA replication and DNA damage, βTrCP instead targets Claspin in a Plk1-dependent manner.[11][12][13]

βTrCP has also emerged as an important player in protein translation, cell grow and survival. In response to mitogens, PDCD4, an inhibitor of the translation initiation factor eIF4A, is rapidly degraded in a βTrCP- and S6K1-dependent manner, allowing efficient protein translation and cell growth.[14] βTrCP also cooperates with mTOR and CK1α to induce the degradation of DEPTOR (an mTOR inhibitor), thereby generating an auto-amplification loop to promote the full activation of mTOR.[15][16][17] At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.[18]

βTrCP also associates with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by regulating the NF-kappaB and the WNT pathways.[19][20]

Interactions

BTRC (gene) has been shown to interact with:

Clinical Significance

βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal,[33] pancreatic,[34] hapatoblastoma,[35] and breast cancers.[36]

References

  1. ↑ Fujiwara T, Suzuki M, Tanigami A, Ikenoue T, Omata M, Chiba T, Tanaka K (Jul 1999). "The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25". Genomics. 58 (1): 104–105. doi:10.1006/geno.1999.5792. PMID 10331953.
  2. ↑ "Entrez Gene: BTRC beta-transducin repeat containing".
  3. ↑ 3.0 3.1 Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R (Jul 1998). "A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif". Mol Cell. 1 (4): 565–574. doi:10.1016/S1097-2765(00)80056-8. PMID 9660940.
  4. ↑ Frescas, D.; Pagano, M. (2008). "Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: Tipping the scales of cancer". Nature Reviews Cancer. 8 (6): 438–449. doi:10.1038/nrc2396. PMC 2711846. PMID 18500245.
  5. ↑ 5.0 5.1 5.2 Busino, L.; Donzelli, M.; Chiesa, M.; Guardavaccaro, D.; Ganoth, D.; Dorrello, N.; Hershko, A.; Pagano, M.; Draetta, G. F. (2003). "Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage". Nature. 426 (6962): 87–91. doi:10.1038/nature02082. PMID 14603323.
  6. ↑ 6.0 6.1 Watanabe, N.; Arai, H.; Nishihara, Y.; Taniguchi, M.; Watanabe, N.; Hunter, T.; Osada, H. (2004). "M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP". Proceedings of the National Academy of Sciences. 101 (13): 4419–4424. doi:10.1073/pnas.0307700101. PMC 384762. PMID 15070733.
  7. ↑ 7.0 7.1 7.2 Guardavaccaro, D.; Kudo, Y.; Boulaire, J.; Barchi, M.; Busino, L.; Donzelli, M.; Margottin-Goguet, F.; Jackson, P. K.; Yamasaki, L.; Pagano, M. (2003). "Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo". Developmental Cell. 4 (6): 799–812. doi:10.1016/S1534-5807(03)00154-0. PMID 12791266.
  8. ↑ 8.0 8.1 Margottin-Goguet, F.; Hsu, J. Y.; Loktev, A.; Hsieh, H. M.; Reimann, J. D.; Jackson, P. K. (2003). "Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase". Developmental Cell. 4 (6): 813–826. doi:10.1016/S1534-5807(03)00153-9. PMID 12791267.
  9. ↑ Guardavaccaro, D.; Frescas, D.; Dorrello, N. V.; Peschiaroli, A.; Multani, A. S.; Cardozo, T.; Lasorella, A.; Iavarone, A.; Chang, S.; Hernando, E.; Pagano, M. (2008). "Control of chromosome stability by the β-TrCP–REST–Mad2 axis". Nature. 452 (7185): 365–369. doi:10.1038/nature06641. PMC 2707768. PMID 18354482.
  10. ↑ 10.0 10.1 Jin, J.; Shirogane, T.; Xu, L.; Nalepa, G.; Qin, J.; Elledge, S. J.; Harper, J. W. (2003). "SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase". Genes & Development. 17 (24): 3062–3074. doi:10.1101/gad.1157503. PMC 305258. PMID 14681206.
  11. ↑ 11.0 11.1 Peschiaroli, A.; Dorrello, N. V.; Guardavaccaro, D.; Venere, M.; Halazonetis, T.; Sherman, N. E.; Pagano, M. (2006). "SCFβTrCP-Mediated Degradation of Claspin Regulates Recovery from the DNA Replication Checkpoint Response". Molecular Cell. 23 (3): 319–329. doi:10.1016/j.molcel.2006.06.013. PMID 16885022.
  12. ↑ 12.0 12.1 Mailand, N.; Bekker-Jensen, S.; Bartek, J.; Lukas, J. (2006). "Destruction of Claspin by SCFβTrCP Restrains Chk1 Activation and Facilitates Recovery from Genotoxic Stress". Molecular Cell. 23 (3): 307–318. doi:10.1016/j.molcel.2006.06.016. PMID 16885021.
  13. ↑ 13.0 13.1 Mamely, I.; Van Vugt, M. A. M.; Smits, V. A.; Semple, J. I.; Lemmens, B.; Perrakis, A.; Medema, R. H.; Freire, R. (2006). "Polo-like Kinase-1 Controls Proteasome-Dependent Degradation of Claspin during Checkpoint Recovery". Current Biology. 16 (19): 1950–1955. doi:10.1016/j.cub.2006.08.026. PMID 16934469.
  14. ↑ 14.0 14.1 Dorrello, N. V.; Peschiaroli, A.; Guardavaccaro, D.; Colburn, N. H.; Sherman, N. E.; Pagano, M. (2006). "S6K1- and TRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth". Science. 314 (5798): 467–471. doi:10.1126/science.1130276. PMID 17053147.
  15. ↑ 15.0 15.1 Duan, S.; Skaar, J. R.; Kuchay, S.; Toschi, A.; Kanarek, N.; Ben-Neriah, Y.; Pagano, M. (2011). "MTOR Generates an Auto-Amplification Loop by Triggering the βTrCP- and CK1α-Dependent Degradation of DEPTOR". Molecular Cell. 44 (2): 317–324. doi:10.1016/j.molcel.2011.09.005. PMC 3212871. PMID 22017877.
  16. ↑ 16.0 16.1 Zhao, Y.; Xiong, X.; Sun, Y. (2011). "DEPTOR, an mTOR Inhibitor, is a Physiological Substrate of SCFβTrCP E3 Ubiquitin Ligase and Regulates Survival and Autophagy". Molecular Cell. 44 (2): 304–316. doi:10.1016/j.molcel.2011.08.029. PMC 3216641. PMID 22017876.
  17. ↑ 17.0 17.1 Gao, D.; Inuzuka, H.; Tan, M. K. M.; Fukushima, H.; Locasale, J. W.; Liu, P.; Wan, L.; Zhai, B.; Chin, Y. R.; Shaik, S.; Lyssiotis, C. A.; Gygi, S. P.; Toker, A.; Cantley, L. C.; Asara, J. M.; Harper, J. W.; Wei, W. (2011). "MTOR Drives Its Own Activation via SCFβTrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR". Molecular Cell. 44 (2): 290–303. doi:10.1016/j.molcel.2011.08.030. PMC 3229299. PMID 22017875.
  18. ↑ 18.0 18.1 Dehan, E.; Bassermann, F.; Guardavaccaro, D.; Vasiliver-Shamis, G.; Cohen, M.; Lowes, K. N.; Dustin, M.; Huang, D. C. S.; Taunton, J.; Pagano, M. (2009). "ΒTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis". Molecular Cell. 33 (1): 109–116. doi:10.1016/j.molcel.2008.12.020. PMC 2655121. PMID 19150432.
  19. ↑ Winston, J. T.; Strack, P.; Beer-Romero, P.; Chu, C. Y.; Elledge, S. J.; Harper, J. W. (1999). "The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro". Genes & Development. 13 (3): 270–283. doi:10.1101/gad.13.3.270. PMC 316433. PMID 9990852.
  20. ↑ 20.0 20.1 Latres, E.; Chiaur, D. S.; Pagano, M. (1999). "The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin". Oncogene. 18 (4): 849–854. doi:10.1038/sj.onc.1202653. PMID 10023660.
  21. ↑ Liu, C.; Kato, Y.; Zhang, Z.; Do, V. M.; Yankner, B. A.; He, X. (1999). "Β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation". Proceedings of the National Academy of Sciences of the United States of America. 96 (11): 6273–6278. doi:10.1073/pnas.96.11.6273. PMC 26871. PMID 10339577.
  22. ↑ 22.0 22.1 22.2 Cenciarelli, C.; Chiaur, D. S.; Guardavaccaro, D.; Parks, W.; Vidal, M.; Pagano, M. (1999). "Identification of a family of human F-box proteins". Current Biology. 9 (20): 1177–1179. doi:10.1016/S0960-9822(00)80020-2. PMID 10531035.
  23. ↑ Semplici F, Meggio F, Pinna LA, Oliviero S (June 2002). "CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation". Oncogene. 21 (25): 3978–87. doi:10.1038/sj.onc.1205574. PMID 12037680.
  24. ↑ 24.0 24.1 24.2 24.3 Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K (January 2000). "Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination". J. Biol. Chem. 275 (4): 2877–84. doi:10.1074/jbc.275.4.2877. PMID 10644755.
  25. ↑ 25.0 25.1 Min, K. -W.; Hwang, J. W.; Lee, J. S.; Park, Y.; Tamura, T. A.; Yoon, J. B. (2003). "TIP120A Associates with Cullins and Modulates Ubiquitin Ligase Activity". Journal of Biological Chemistry. 278 (18): 15905–15910. doi:10.1074/jbc.M213070200. PMID 12609982.
  26. ↑ Mantovani F, Banks L (October 2003). "Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor". J. Biol. Chem. 278 (43): 42477–86. doi:10.1074/jbc.M302799200. PMID 12902344.
  27. ↑ 27.0 27.1 Spencer E, Jiang J, Chen ZJ (February 1999). "Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP". Genes Dev. 13 (3): 284–94. doi:10.1101/gad.13.3.284. PMC 316434. PMID 9990853.
  28. ↑ Fong A, Sun SC (June 2002). "Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100". J. Biol. Chem. 277 (25): 22111–4. doi:10.1074/jbc.C200151200. PMID 11994270.
  29. ↑ Vatsyayan J, Qing G, Xiao G, Hu J (September 2008). "SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing". EMBO Rep. 9 (9): 885–90. doi:10.1038/embor.2008.122. PMC 2529344. PMID 18617892.
  30. ↑ Westbrook, T. F.; Hu, G.; Ang, X. L.; Mulligan, P.; Pavlova, N. N.; Liang, A.; Leng, Y.; Maehr, R.; Shi, Y.; Harper, J. W.; Elledge, S. J. (2008). "SCFβTRCPControls Oncogenic Transformation and Neural Differentiation Through REST Degradation". Nature. 452 (7185): 370–374. doi:10.1038/nature06780. PMC 2688689. PMID 18354483.
  31. ↑ Strack, P.; Caligiuri, M.; Pelletier, M.; Boisclair, M.; Theodoras, A.; Beer-Romero, P.; Glass, S.; Parsons, T.; Copeland, R. A.; Auger, K. R.; Benfield, P.; Brizuela, L.; Rolfe, M. (2000). "SCFβ-TRCP and phosphorylation dependent ubiquitination of IκBα catalyzed by Ubc3 and Ubc4". Oncogene. 19 (31): 3529–3536. doi:10.1038/sj.onc.1203647. PMID 10918611.
  32. ↑ "Molecular Interaction Database".
  33. ↑ Ougolkov, A.; Zhang, B.; Yamashita, K.; Bilim, V.; Mai, M.; Fuchs, S. Y.; Minamoto, T. (2004). "Associations Among -TrCP, an E3 Ubiquitin Ligase Receptor, -Catenin, and NF- B in Colorectal Cancer". JNCI Journal of the National Cancer Institute. 96 (15): 1161–1170. doi:10.1093/jnci/djh219. PMID 15292388.
  34. ↑ Muerkoster, S.; Arlt, A.; Sipos, B.; Witt, M.; Grossmann, M.; Klöppel, G.; Kalthoff, H.; Fölsch, U. R.; Schäfer, H. (2005). "Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit TRCP1 Relates to Constitutive Nuclear Factor- B Activation and Chemoresistance in Pancreatic Carcinoma Cells". Cancer Research. 65 (4): 1316–1324. doi:10.1158/0008-5472.CAN-04-1626. PMID 15735017.
  35. ↑ Koch, A.; Waha, A.; Hartmann, W.; Hrychyk, A.; Schüller, U.; Waha, A.; Wharton Jr, K. A.; Fuchs, S. Y.; Von Schweinitz, D.; Pietsch, T. (2005). "Elevated Expression of Wnt Antagonists is a Common Event in Hepatoblastomas". Clinical Cancer Research. 11 (12): 4295–4304. doi:10.1158/1078-0432.CCR-04-1162. PMID 15958610.
  36. ↑ Spiegelman, V. S.; Tang, W.; Chan, A. M.; Igarashi, M.; Aaronson, S. A.; Sassoon, D. A.; Katoh, M.; Slaga, T. J.; Fuchs, S. Y. (2002). "Induction of Homologue of Slimb Ubiquitin Ligase Receptor by Mitogen Signaling". Journal of Biological Chemistry. 277 (39): 36624–36630. doi:10.1074/jbc.M204524200. PMID 12151397.

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