BTRC (gene)

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. Subsequently, βTrCP was shown to regulate multiple cellular processes by mediating the degradation of various targets. 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, whereas in G2, βTrCP contributes to CDK1 activation by targeting the kinase WEE1 for degradation. In early mitosis, βTrCP mediates the degradation of EMI1, 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 microtubules.

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, 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.

βTrCP has also emerged as an important player in protein translation, cell growth 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. Another target of βTrCP that is involved in protein translation is eEF2K, which inhibits translation elongation by phosphorylating eukaryotic Elongation Factor 2 (eEF2) and decreasing its affinity for the ribosome. 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. At the same time, βTrCP mediates the degradation of the pro-apoptotic protein BimEL to promote cell survival.

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. βTrCP has also been shown to regulate centriole disengagement and licensing. βTrCP target the intercentrosomal linker protein Cep68 in prometaphase, which contributes to centriole disengagement and subsequent centriole separation.

Interactions

BTRC (gene) has been shown to interact with:

• β-catenin,
• BimEL1
• Cdc25A,
• CDC34,
• Claspin,
• CUL1,
• DEPTOR,
• DLG1,
• EMI1,
• FBXW11,
• IκBα,
• NFKB2,
• PDCD4,
• RELA,
• REST,
• SKP1A, and
• WEE1.
• C22orf25

Clinical Significance

βTrCP behaves as an oncoprotein in some tissues. Elevated levels of βTrCP expression have been found in colorectal, pancreatic, hepatoblastoma, and breast cancers.

References

References

1. (May 1999). "The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25". Genomics.
2. "Entrez Gene: BTRC beta-transducin repeat containing".
3. (March 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". Molecular Cell.
4. (June 2008). "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer". Nature Reviews. Cancer.
5. (November 2003). "Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage". Nature.
6. (March 2004). "M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP". Proceedings of the National Academy of Sciences of the United States of America.
7. (June 2003). "Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo". Developmental Cell.
8. (June 2003). "Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase". Developmental Cell.
9. (March 2008). "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis". Nature.
10. (December 2003). "SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase". Genes & Development.
11. (August 2006). "SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response". Molecular Cell.
12. (August 2006). "Destruction of Claspin by SCFbetaTrCP restrains Chk1 activation and facilitates recovery from genotoxic stress". Molecular Cell.
13. (October 2006). "Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery". Current Biology.
14. (October 2006). "S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth". Science.
15. Sci Signal. 2012 Jun 5;5(227):ra40. doi: 10.1126/scisignal.2002718. SCFβTrCP-mediated degradation of eEF2K couples protein synthesis elongation to the G2 DNA damage checkpoint. Kruiswijk F., Yuniati L., Magliozzi R., Bolder R., Lim R., Low T., Heck A., Pagano M., and Guardavaccaro D.
16. (October 2011). "mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR". Molecular Cell.
17. (October 2011). "DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy". Molecular Cell.
18. (October 2011). "mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR". Molecular Cell.
19. (January 2009). "betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis". Molecular Cell.
20. (February 1999). "The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro". Genes & Development.
21. (January 1999). "The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin". Oncogene.
22. Nature cell biology. 2015;17(1):31-43. doi:10.1038/ncb3076. Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing. Pagan JK, Marzio A, Jones MJ, Saraf A, Jallepalli PV, Florens L, Washburn MP, Pagano M.
23. (May 1999). "beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation". Proceedings of the National Academy of Sciences of the United States of America.
24. (October 1999). "Identification of a family of human F-box proteins". Current Biology.
25. (June 2002). "CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation". Oncogene.
26. (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". The Journal of Biological Chemistry.
27. (October 2003). "Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor". The Journal of Biological Chemistry.
28. (January 2000). "Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination". The Journal of Biological Chemistry.
29. (June 2002). "Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100". The Journal of Biological Chemistry.
30. (September 2008). "SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing". EMBO Reports.
31. (March 2008). "SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation". Nature.
32. (July 2000). "SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4". Oncogene.
33. "Molecular Interaction Database".
34. (August 2004). "Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer". Journal of the National Cancer Institute.
35. (February 2005). "Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells". Cancer Research.
36. (June 2005). "Elevated expression of Wnt antagonists is a common event in hepatoblastomas". Clinical Cancer Research.
37. (September 2002). "Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling". The Journal of Biological Chemistry.