SKP2

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S-phase kinase-associated protein 2 (p45)

PDB rendering based on 1fqv.
Identifiers
Symbols SKP2; FBL1; FBXL1; FLB1; MGC1366
External IDs OMIM: 601436 MGI: 1351663 HomoloGene: 55942 GeneCards: SKP2 Gene
RNA expression pattern
PBB GE SKP2 210567 s at tn.png
PBB GE SKP2 203625 x at tn.png
PBB GE SKP2 211042 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6502 27401
Ensembl ENSG00000145604 ENSMUSG00000054115
UniProt Q13309 Q4KMS0
RefSeq (mRNA) NM_005983.2 NM_013787
RefSeq (protein) NP_005974.2 NP_038815
Location (UCSC) Chr 5:
36.15 – 36.18 Mb		 Chr 15:
9.04 – 9.07 Mb
PubMed search [1] [2]

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.[1][2]

Contents

[edit] Function

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box domain.[3] The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which often—but not always—recognize substrates in a phosphorylation-dependent manner. The F-box proteins are divided into three classes: Fbxws containing WD40 repeat domains, Fbxls containing leucine-rich repeats, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs[4]. The protein encoded by this gene belongs to the Fbxls class; in addition to an F-box, this protein contains 10 tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms.

Skp2 forms a stable complex with the cyclin A-CDK2 S-phase kinase. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S, G2, and the initial part of the M phase.[5][6]

The degradation of p27 via Skp2 requires the accessory protein CKS1B.[7][8] To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2.[9][10]

Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase.[11][12][13][14][15]

[edit] Clinical significance

Skp2 behaves as an oncogene in cell systems[16] and is an established protooncogene causally involved in the pathogenesis of lymphomas.[17] Higher levels of Skp2 expression bode poorly for breast cancer.[18][19]

Skp2 is a potential target for pten-deficient cancers.[20]

[edit] Interactions

SKP2 has been shown to interact with:


[edit] References

  1. ^ Demetrick DJ, Zhang H, Beach DH (Jul 1996). "Chromosomal mapping of the genes for the human CDK2/cyclin A-associated proteins p19 (SKP1A and SKP1B) and p45 (SKP2)". Cytogenet Cell Genet 73 (1–2): 104–7. doi:10.1159/000134318. PMID 8646875. 
  2. ^ "Entrez Gene: SKP2 S-phase kinase-associated protein 2 (p45)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6502. 
  3. ^ Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ (July 1996). "SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box". Cell 86 (2): 263–74. doi:10.1016/S0092-8674(00)80098-7. PMID 8706131. 
  4. ^ Kipreos ET, Pagano M (2000). "The F-box protein family". Genome Biol. 1 (5): REVIEWS3002. doi:10.1186/gb-2000-1-5-reviews3002. PMC 138887. PMID 11178263. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138887. 
  5. ^ Carrano AC, Eytan E, Hershko A, Pagano M (August 1999). "SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27". Nat. Cell Biol. 1 (4): 193–9. doi:10.1038/12013. PMID 10559916. 
  6. ^ Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H (June 1999). "p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27". Curr. Biol. 9 (12): 661–4. doi:10.1016/S0960-9822(99)80290-5. PMID 10375532. 
  7. ^ a b c Sitry D, Seeliger MA, Ko TK, Ganoth D, Breward SE, Itzhaki LS, Pagano M, Hershko A (November 2002). "Three different binding sites of Cks1 are required for p27-ubiquitin ligation". J. Biol. Chem. 277 (44): 42233–40. doi:10.1074/jbc.M205254200. PMID 12140288. 
  8. ^ a b Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A (March 2001). "The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27". Nat. Cell Biol. 3 (3): 321–4. doi:10.1038/35060126. PMID 11231585. 
  9. ^ Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M (March 2004). "Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase". Nature 428 (6979): 190–3. doi:10.1038/nature02330. PMID 15014502. 
  10. ^ Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG (March 2004). "Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex". Nature 428 (6979): 194–8. doi:10.1038/nature02381. PMID 15014503. 
  11. ^ Rodier G, Coulombe P, Tanguay PL, Boutonnet C, Meloche S (February 2008). "Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APCCdh1 in G1 phase". EMBO J. 27 (4): 679–91. doi:10.1038/emboj.2008.6. PMC 2262036. PMID 18239684. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2262036. 
  12. ^ Bashir T, Pagan JK, Busino L, Pagano M (March 2010). "Phosphorylation of Ser72 is dispensable for Skp2 assembly into an active SCF ubiquitin ligase and its subcellular localization". Cell Cycle 9 (5): 971–4. doi:10.4161/cc.9.5.10914. PMID 20160477. 
  13. ^ Boutonnet C, Tanguay PL, Julien C, Rodier G, Coulombe P, Meloche S (March 2010). "Phosphorylation of Ser72 does not regulate the ubiquitin ligase activity and subcellular localization of Skp2". Cell Cycle 9 (5): 975–9. doi:10.4161/cc.9.5.10915. PMID 20160482. 
  14. ^ Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W (April 2009). "Phosphorylation by Akt1 Promotes Skp2 Cytoplasmic Localization and Impairs APC/Cdh1-mediated Skp2 Destruction". Nat. Cell Biol. 11 (4): 397–408. doi:10.1038/ncb1847. PMC 2910589. PMID 19270695. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2910589. 
  15. ^ Wang H, Cui J, Bauzon F, Zhu L (March 2010). "A comparison between Skp2 and FOXO1 for their cytoplasmic localization by Akt1". Cell Cycle 9 (5): 1021–2. doi:10.4161/cc.9.5.10916. PMC 2990537. PMID 20160512. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2990537. 
  16. ^ Carrano AC, Pagano M (June 2001). "Role of the F-Box Protein Skp2 in Adhesion-Dependent Cell Cycle Progression". J. Cell Biol. 153 (7): 1381–90. doi:10.1083/jcb.153.7.1381. PMC 2150734. PMID 11425869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2150734. 
  17. ^ Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G, Pagano M (February 2001). "Role of the F-box protein Skp2 in lymphomagenesis". Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2515–20. doi:10.1073/pnas.041475098. PMC 30169. PMID 11226270. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=30169. 
  18. ^ http://clincancerres.aacrjournals.org/content/12/4/1215.abstract "Significance of skp2 expression in primary breast cancer" 2006
  19. ^ Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M (September 2002). "Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer". J. Clin. Invest. 110 (5): 633–41. doi:10.1172/JCI15795. PMC 151109. PMID 12208864. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151109. 
  20. ^ Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, Chan CH, Yang WL, Wang J, Egia A, Nakayama KI, Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PP (March 2010). "Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence". Nature 464 (7287): 374–9. doi:10.1038/nature08815. PMC 2928066. PMID 20237562. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2928066. Lay summary – ScienceDaily. 
  21. ^ a b Rosner M, Hengstschläger M (November 2004). "Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2". J. Biol. Chem. 279 (47): 48707–15. doi:10.1074/jbc.M405528200. PMID 15355997. 
  22. ^ a b c d Marti A, Wirbelauer C, Scheffner M, Krek W (May 1999). "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nat. Cell Biol. 1 (1): 14–9. doi:10.1038/8984. PMID 10559858. 
  23. ^ Yam CH, Ng RW, Siu WY, Lau AW, Poon RY (January 1999). "Regulation of Cyclin A-Cdk2 by SCF Component Skp1 and F-Box Protein Skp2". Mol. Cell. Biol. 19 (1): 635–45. PMC 83921. PMID 9858587. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=83921. 
  24. ^ Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A (July 2003). "Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase". J. Biol. Chem. 278 (28): 25752–7. doi:10.1074/jbc.M301774200. PMID 12730199. 
  25. ^ a b Wang W, Ungermannova D, Chen L, Liu X (August 2003). "A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1". J. Biol. Chem. 278 (34): 32390–6. doi:10.1074/jbc.M305241200. PMID 12813041. 
  26. ^ Fujita N, Sato S, Katayama K, Tsuruo T (August 2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. 277 (32): 28706–13. doi:10.1074/jbc.M203668200. PMID 12042314. 
  27. ^ Calvisi DF, Pinna F, Meloni F, Ladu S, Pellegrino R, Sini M, Daino L, Simile MM, De Miglio MR, Virdis P, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM (June 2008). "Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma". Cancer Res. 68 (11): 4192–200. doi:10.1158/0008-5472.CAN-07-6157. PMID 18519678. 
  28. ^ Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP (October 2005). "Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase". Mol. Cell 20 (1): 9–19. doi:10.1016/j.molcel.2005.09.003. PMID 16209941. 
  29. ^ a b Li X, Zhao Q, Liao R, Sun P, Wu X (August 2003). "The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation". J. Biol. Chem. 278 (33): 30854–8. doi:10.1074/jbc.C300251200. PMID 12840033. 
  30. ^ a b Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982. 
  31. ^ Lisztwan J, Marti A, Sutterlüty H, Gstaiger M, Wirbelauer C, Krek W (January 1998). "Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway". EMBO J. 17 (2): 368–83. doi:10.1093/emboj/17.2.368. PMC 1170388. PMID 9430629. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1170388. 
  32. ^ Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP (April 2002). "Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex". Nature 416 (6882): 703–9. doi:10.1038/416703a. PMID 11961546. 
  33. ^ Menon S, Tsuge T, Dohmae N, Takio K, Wei N (2008). "Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome". BMC Biochem. 9: 1. doi:10.1186/1471-2091-9-1. PMC 2265268. PMID 18173839. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2265268. 
  34. ^ Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B (March 2002). "Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication". Mol. Cell 9 (3): 481–91. doi:10.1016/S1097-2765(02)00467-7. PMID 11931757. 
  35. ^ Strack P, Caligiuri M, Pelletier M, Boisclair M, Theodoras A, Beer-Romero P, Glass S, Parsons T, Copeland RA, Auger KR, Benfield P, Brizuela L, Rolfe M (July 2000). "SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4". Oncogene 19 (31): 3529–36. doi:10.1038/sj.onc.1203647. PMID 10918611. 
  36. ^ Ng RW, Arooz T, Yam CH, Chan IW, Lau AW, Poon RY (November 1998). "Characterization of the cullin and F-box protein partner Skp1". FEBS Lett. 438 (3): 183–9. doi:10.1016/S0014-5793(98)01299-X. PMID 9827542. 
  37. ^ Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP (November 2000). "Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex". Nature 408 (6810): 381–6. doi:10.1038/35042620. PMID 11099048. 
  38. ^ Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (October 1999). "Identification of a family of human F-box proteins". Curr. Biol. 9 (20): 1177–9. doi:10.1016/S0960-9822(00)80020-2. PMID 10531035. 


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