SKP2

S-phase kinase-associated protein 2, E3 ubiquitin protein ligase

PDB rendering based on 2ast.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsSKP2 ; FBL1; FBXL1; FLB1; p45
External IDsOMIM: 601436 MGI: 1351663 HomoloGene: 55942 GeneCards: SKP2 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez650227401
EnsemblENSG00000145604ENSMUSG00000054115
UniProtQ13309Q9Z0Z3
RefSeq (mRNA)NM_001243120NM_001285980
RefSeq (protein)NP_001230049NP_001272909
Location (UCSC)Chr 5:
36.15 – 36.18 Mb		Chr 15:
9.11 – 9.14 Mb
PubMed search

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

Structure and function

Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-140 position and the C-terminal region forming a concave surface consisting of ten leucine-rich repeats (LRRs).[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. In this SCF complex, Skp2 acts as the substrate recognition factor.[4][5][6]

F-box Domain

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.[7] 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. After the tenth LRR, the ~30-residue C-terminal tail turns back towards the first LRR, forming what has been referred to as a ‘safety-belt’ that might aid to pin down substrates into the concave surface formed by the LRRs.[8]

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 phase, and the initial part of the M phase.[9][10]

The degradation of p27 via Skp2 requires the accessory protein CKS1B.[11][12] 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.[13][14]

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.[15][16][17][18][19]

Role in cell cycle regulation

Progression through the cell cycle is tightly regulated by cyclin-dependent kinases (CDKs), and their interactions with cyclins and CDK inhibitors (CKIs). Relative amounts of these signals oscillate during each stage of the cell cycle due to periodic proteolysis;[20] the ubiquitin-proteasome system mediates the degradation of these mitotic regulatory proteins, controlling their intracellular concentrations.[21][22] These and other proteins are recognized and degraded by the proteasome from the sequential action of three enzymes: E1 (ubiquitin-activating enzyme), one of many E2s (ubiquitin-conjugating enzyme), and one of many E3 ubiquitin ligase.[23] The specificity of ubiquitination is provided by the E3 ligases; these ligases physically interact with the target substrates. Skp2 is the substrate recruiting component of the SCFSkp2 complex, which targets cell cycle control elements, such as p27 and p21.

Clinical significance

Skp2 behaves as an oncogene in cell systems[24] and is an established protooncogene causally involved in the pathogenesis of lymphomas.[25] One of the most critical CDK inhibitors involved in cancer pathogenesis is p27Kip1, which is involved primarily in inhibiting cyclin E-CDK2 complexes (and to a lesser extent cyclin D-CDK4 complexes).[26] Levels of p27Kip1 (like all other CKIs) rise and fall in cells as they either exit or re-enter the cell cycle, these levels are not modulated at the transcriptional level, but by the actions of the SCFSkp2 complex in recognizing p27Kip1 and tagging it for destruction in the proteasome system.[20] It has been shown that as cells enter G0 phase, reducing levels of Skp2 explain the increase in p27Kip1, creating an apparent inverse relationship between Skp2 and p27Kip1.[13] Robust evidence has been amassed that strongly suggests Skp2 plays an important role in cancer.

Overexpression

Overexpression of Skp2 is frequently observed in human cancer progression and metastasis, and evidence suggests that Skp2 plays a proto-oncogenic role both in vitro and in vivo.[4] Skp2 overexpression has been seen in: lymphomas,[27] prostate cancer,[28] melanoma,[29] nasopharyngeal carcinoma,[30][31] pancreatic cancer,[32] and breast carcinomas.[33][34] Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer.[35][36] As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model.[37] By extension of this fact, Skp2 inactivation profoundly restricts cancer development by triggering a massive cellular senescence and/or apoptosis response that is surprisingly observed only in oncogenic conditions in vivo.[38] This response is triggered in a p19Arf/p53-independent, but p27-dependent manner.[38]

Using a Skp2 knockout mouse model, multiple groups have shown Skp2 is required for cancer development in different conditions of tumor promotion, including PTEN, ARF, pRB in activation as well as Her2/Neu overexpression.[39]

Genetic approaches have demonstrated that Skp2 deficiency inhibits cancer development in multiple mouse models by inducing p53-independent cellular senescence and blocking Akt-mediated aerobic glycolysis. Akt activation by Skp2 is linked to aerobic glycolysis, as Skp2 deficiency impairs Akt activation, Glut1 expression, and glucose uptake thereby promoting cancer development.[40]

Potential use as a clinical target

Skp2 is of considerable interest as a novel and attractive target for cancer therapeutical development, as disrupting the SCF complex will result in increased levels of p27, which will inhibit aberrant cellular proliferation. Although Skp2 is an enzyme, its function requires the assembly of the other members of the SCF complex. As Skp2 is the rate-limiting component of the SCF complex, effective inhibitors should be focused on the interfaces of Skp2 with the other members of the SCF complex, which is much more difficult than traditional enzyme inhibition. Small molecule inhibitors of the binding site between Skp2 and the accessory protein Cks1 have been discovered, and these inhibitors induce p27 accumulation in a Skp2-dependent manner and promote cell cycle arrest.[41] Another recent discovery were inhibitors of the Skp1/Skp2 interface that resulted in: restoring p27 levels, suppressing survival, trigger p53-independent senescence, exhibit potent antitumor activity in multiple animal models, and were also interestingly found to affect Akt-mediated glycolysis.[42] Skp2 is a potential target for pten-deficient cancers.[38]

Interactions

SKP2 has been shown to interact with:

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)".
  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. ↑ 4.0 4.1 Chan CH, Lee SW, Wang J, Lin HK (2010). "Regulation of Skp2 expression and activity and its role in cancer progression". ScientificWorldJournal 10: 1001–15. doi:10.1100/tsw.2010.89. PMID 20526532.
  5. ↑ 5.0 5.1 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.
  6. ↑ Nakayama KI, Nakayama K (June 2005). "Regulation of the cell cycle by SCF-type ubiquitin ligases". Semin. Cell Dev. Biol. 16 (3): 323–33. doi:10.1016/j.semcdb.2005.02.010. PMID 15840441.
  7. ↑ Kipreos ET, Pagano M (2000). "The F-box protein family". Genome Biol. 1 (5): reviews3002.1–reviews3002.7. doi:10.1186/gb-2000-1-5-reviews3002. PMC 138887. PMID 11178263.
  8. ↑ Cardozo T, Pagano M (September 2004). "The SCF ubiquitin ligase: insights into a molecular machine". Nat. Rev. Mol. Cell Biol. 5 (9): 739–51. doi:10.1038/nrm1471. PMID 15340381.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 11.2 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 13.0 13.1 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 20.0 20.1 Murray AW (January 2004). "Recycling the cell cycle: cyclins revisited". Cell 116 (2): 221–34. doi:10.1016/S0092-8674(03)01080-8. PMID 14744433.
  21. ↑ Weissman AM (March 2001). "Themes and variations on ubiquitylation". Nat. Rev. Mol. Cell Biol. 2 (3): 169–78. doi:10.1038/35056563. PMID 11265246.
  22. ↑ Pickart CM (January 2004). "Back to the future with ubiquitin". Cell 116 (2): 181–90. doi:10.1016/S0092-8674(03)01074-2. PMID 14744430.
  23. ↑ Frescas D, Pagano M (June 2008). "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer". Nat. Rev. Cancer 8 (6): 438–49. doi:10.1038/nrc2396. PMC 2711846. PMID 18500245.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M (October 2002). "Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer". Nat. Med. 8 (10): 1136–44. doi:10.1038/nm762. PMID 12244303.
  27. ↑ Seki R, Okamura T, Koga H, Yakushiji K, Hashiguchi M, Yoshimoto K, Ogata H, Imamura R, Nakashima Y, Kage M, Ueno T, Sata M (August 2003). "Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma". Am. J. Hematol. 73 (4): 230–5. doi:10.1002/ajh.10379. PMID 12879424.
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  29. ↑ Rose AE, Wang G, Hanniford D, Monni S, Tu T, Shapiro RL, Berman RS, Pavlick AC, Pagano M, Darvishian F, Mazumdar M, Hernando E, Osman I (February 2011). "Clinical relevance of SKP2 alterations in metastatic melanoma". Pigment Cell Melanoma Res 24 (1): 197–206. doi:10.1111/j.1755-148X.2010.00784.x. PMC 3341662. PMID 20883453.
  30. ↑ Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY (January 2009). "Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients". Int. J. Radiat. Oncol. Biol. Phys. 73 (1): 202–7. doi:10.1016/j.ijrobp.2008.04.008. PMID 18538504.
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  33. ↑ Radke S, Pirkmaier A, Germain D (May 2005). "Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer". Oncogene 24 (21): 3448–58. doi:10.1038/sj.onc.1208328. PMID 15782142.
  34. ↑ Zheng WQ, Zheng JM, Ma R, Meng FF, Ni CR (October 2005). "Relationship between levels of Skp2 and P27 in breast carcinomas and possible role of Skp2 as targeted therapy". Steroids 70 (11): 770–4. doi:10.1016/j.steroids.2005.04.012. PMID 16024059.
  35. ↑ Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M (February 2006). "Significance of skp2 expression in primary breast cancer". Clin. Cancer Res. 12 (4): 1215–20. doi:10.1158/1078-0432.CCR-05-1709. PMID 16489076.
  36. ↑ 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.
  37. ↑ Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, Yang WL, Erdjument-Bromage H, Nakayama KI, Nimer S, Tempst P, Pandolfi PP (April 2009). "Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB". Nat. Cell Biol. 11 (4): 420–32. doi:10.1038/ncb1849. PMC 2830812. PMID 19270694.
  38. ↑ 38.0 38.1 38.2 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. Lay summary – ScienceDaily.
  39. ↑ Zhang Y, Yang HY, Zhang XC, Yang H, Tsai M, Lee MH (September 2004). "Tumor suppressor ARF inhibits HER-2/neu-mediated oncogenic growth". Oncogene 23 (42): 7132–43. doi:10.1038/sj.onc.1207918. PMID 15273726.
  40. ↑ Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama KI, Lin HK (May 2012). "The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis". Cell 149 (5): 1098–111. doi:10.1016/j.cell.2012.02.065. PMC 3586339. PMID 22632973.
  41. ↑ Wu L, Grigoryan AV, Li Y, Hao B, Pagano M, Cardozo TJ (December 2012). "Specific small molecule inhibitors of Skp2-mediated p27 degradation". Chem. Biol. 19 (12): 1515–24. doi:10.1016/j.chembiol.2012.09.015. PMC 3530153. PMID 23261596.
  42. ↑ Chan CH, Morrow JK, Li CF et al. (August 2013). "Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression". Cell 154 (3): 556–68. doi:10.1016/j.cell.2013.06.048. PMID 23911321.
  43. ↑ 43.0 43.1 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.
  44. ↑ 44.0 44.1 44.2 44.3 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 47.0 47.1 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 51.0 51.1 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.
  52. ↑ 52.0 52.1 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.
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  58. ↑ 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.
  59. ↑ 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.