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Gene Review

SKP2  -  S-phase kinase-associated protein 2, E3...

Homo sapiens

Synonyms: Cyclin-A/CDK2-associated protein p45, F-box protein Skp2, F-box/LRR-repeat protein 1, FBL1, FBXL1, ...
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Disease relevance of SKP2

  • This study provides evidence of a role for an F-box protein in oncogenesis and establishes SKP2 as a protooncogene causally involved in the pathogenesis of lymphomas [1].
  • Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes [2].
  • Our earlier studies revealed SKP2 as a target gene within the 5p13 amplicon that is often seen in small-cell lung cancers [2].
  • Elevated expression of SKP2 correlated significantly with positive lymph node metastasis (P = 0.007), with stage II or higher of the international TNM classification (P = 0.014), with poor or moderate differentiation (P < 0.001), and with the presence of squamous cell carcinoma (P = 0.037) [2].
  • Conversely, in human glioblastoma cells, ectopic PTEN expression leads to p27 accumulation, which is accompanied by a reduction of SKP2 [3].
  • Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05) [4].

High impact information on SKP2

  • In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130 [5].
  • The phosphorylated Thr187 side chain of p27(Kip1) is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both [6].
  • The regulation of antigen receptor gene assembly by Skp2-SCF provides an unexpected and direct mechanistic link between DNA recombination and the cell cycle [7].
  • We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation [8].
  • These data suggest that Skp2 functions to connect Myc activity and destruction, and reveal an unexpected oncoprotein connection that may play an important role in controlling cell growth in normal and cancer cells [9].

Chemical compound and disease context of SKP2


Biological context of SKP2

  • SKP2 accumulation is often deregulated in cancer, which indicates that temporal control of SKP2 is essential for normal cell proliferation [15].
  • CDK9 protein levels remained unchanged in human cells entering and progressing through the cell cycle from G(0), despite dramatic changes in SKP2 expression [16].
  • Finally, downregulation of endogenous SKP2 gene expression by interfering RNA had no effect on CDK9 protein levels, whereas p27 protein levels increased dramatically [16].
  • Activation of CDK2 and binding to SKP2 or p27(KIP1) were not affected by the phosphorylation of Ser-154 [17].
  • Reduction of SKP2 expression by transfection of an anti-sense oligonucleotide inhibited invasion and migration of NSCLC cells in culture [2].

Anatomical context of SKP2

  • SKP2 exhibited amplification in 5 (20%) of 25 cell lines derived from NSCLC, and the transcript was overexpressed in 11 (44%) of the 25 lines [2].
  • Moreover, adenoviral-mediated expression of SKP2 accelerates downregulation of endogenous hyperphosphorylated p130 in mitogen-stimulated T98G cells and primary WI38 fibroblasts [18].
  • We found that the supplementation of Skp2-Skp1 and substrate (along with further components necessary for substrate presentation to the ubiquitin ligase) to extracts of HeLa cells synergistically increased levels of neddylated Cul1 [19].
  • RESULTS: Western blot analysis showed that high Skp2 expression was observed in 57 (57.6%) cases and significantly correlated with unfavorable cytogenetics (P = 0.035) but not with age, white blood cell count, serum lactic dehydrogenase level, and the French-American-British subtype [20].
  • RESULTS: Skp2 staining was localized in the nuclei of the glandular cells of the proliferative phase endometrium, and endometrial hyperplasia and carcinoma cells [21].

Associations of SKP2 with chemical compounds


Physical interactions of SKP2

  • We show that Skp1 can bind to Skp2 in vitro using recombinant proteins, and in vivo using the yeast two-hybrid system [26].
  • PURPOSE: Skp2 interacts with the degradation of cyclin-dependent kinase inhibitor p27 [21].
  • In vitro, SKP2 specifically interacted with the cyclin E peptide containing the phosphorylated-Thr380 but not with a cognate nonphosphorylated peptide [27].
  • Here we show that the Skp2-binding site of Cks1 is located on a region including the alpha2- and alpha1-helices and their immediate vicinity, well separated from the other two binding sites [28].
  • We showed that the F-box protein Skp2 specifically interacted with human Cdt1 in a phosphorylation-dependent manner [29].
  • We also provide evidence that Skp2 interacts physiologically with E2F-1 and stimulates its transcriptional activity toward the cyclin E promoter [30].

Enzymatic interactions of SKP2


Regulatory relationships of SKP2


Other interactions of SKP2

  • SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 [35].
  • Skp1, together with F-box proteins like Skp2, are part of ubiquitin-ligase E3 complexes that target many cell cycle regulators for ubiquitination-mediated proteolysis [36].
  • CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2 [16].
  • Moreover, we provide evidence for a physical association between Cul4A, DDB1, and Skp2 [37].
  • Exogenous Skp2 prevented growth arrest of MCF-7 cells by antiestrogen, coinciding with decreased p27Kip1 expression [38].

Analytical, diagnostic and therapeutic context of SKP2


  1. Role of the F-box protein Skp2 in lymphomagenesis. Latres, E., Chiarle, R., Schulman, B.A., Pavletich, N.P., Pellicer, A., Inghirami, G., Pagano, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  2. Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes. Yokoi, S., Yasui, K., Mori, M., Iizasa, T., Fujisawa, T., Inazawa, J. Am. J. Pathol. (2004) [Pubmed]
  3. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2). Mamillapalli, R., Gavrilova, N., Mihaylova, V.T., Tsvetkov, L.M., Wu, H., Zhang, H., Sun, H. Curr. Biol. (2001) [Pubmed]
  4. Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer. Chiappetta, G., De Marco, C., Quintiero, A., Califano, D., Gherardi, S., Malanga, D., Scrima, M., Montero-Conde, C., Cito, L., Monaco, M., Motti, M.L., Pasquinelli, R., Agosti, V., Robledo, M., Fusco, A., Viglietto, G. Endocr. Relat. Cancer (2007) [Pubmed]
  5. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Tedesco, D., Lukas, J., Reed, S.I. Genes Dev. (2002) [Pubmed]
  6. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Hao, B., Zheng, N., Schulman, B.A., Wu, G., Miller, J.J., Pagano, M., Pavletich, N.P. Mol. Cell (2005) [Pubmed]
  7. Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Jiang, H., Chang, F.C., Ross, A.E., Lee, J., Nakayama, K., Nakayama, K., Desiderio, S. Mol. Cell (2005) [Pubmed]
  8. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. von der Lehr, N., Johansson, S., Wu, S., Bahram, F., Castell, A., Cetinkaya, C., Hydbring, P., Weidung, I., Nakayama, K., Nakayama, K.I., Söderberg, O., Kerppola, T.K., Larsson, L.G. Mol. Cell (2003) [Pubmed]
  9. Skp2 regulates Myc protein stability and activity. Kim, S.Y., Herbst, A., Tworkowski, K.A., Salghetti, S.E., Tansey, W.P. Mol. Cell (2003) [Pubmed]
  10. The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells. Lu, L., Schulz, H., Wolf, D.A. BMC Cell Biol. (2002) [Pubmed]
  11. Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Yang, G., Ayala, G., De Marzo, A., Tian, W., Frolov, A., Wheeler, T.M., Thompson, T.C., Harper, J.W. Clin. Cancer Res. (2002) [Pubmed]
  12. Dibutyryl cAMP stimulates the proliferation of SH-SY5Y human neuroblastoma cells by up-regulating Skp2 protein. Cho, C.H., Seo, M., Lee, Y.I., Kim, S.Y., Youn, H.D., Juhnn, Y.S. J. Cancer Res. Clin. Oncol. (2007) [Pubmed]
  13. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Shapira, M., Ben-Izhak, O., Linn, S., Futerman, B., Minkov, I., Hershko, D.D. Cancer (2005) [Pubmed]
  14. Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells. Koga, H., Harada, M., Ohtsubo, M., Shishido, S., Kumemura, H., Hanada, S., Taniguchi, E., Yamashita, K., Kumashiro, R., Ueno, T., Sata, M. Hepatology (2003) [Pubmed]
  15. Mechanism of cell-cycle control: ligating the ligase. Lin, D.I., Diehl, J.A. Trends Biochem. Sci. (2004) [Pubmed]
  16. CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2. Garriga, J., Bhattacharya, S., Calbó, J., Marshall, R.M., Truongcao, M., Haines, D.S., Graña, X. Mol. Cell. Biol. (2003) [Pubmed]
  17. Degradation of cyclin A does not require its phosphorylation by CDC2 and cyclin-dependent kinase 2. Yam, C.H., Siu, W.Y., Lau, A., Poon, R.Y. J. Biol. Chem. (2000) [Pubmed]
  18. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Bhattacharya, S., Garriga, J., Calbó, J., Yong, T., Haines, D.S., Graña, X. Oncogene (2003) [Pubmed]
  19. Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. Bornstein, G., Ganoth, D., Hershko, A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  20. Elevated S-phase kinase-associated protein 2 protein expression in acute myelogenous leukemia: its association with constitutive phosphorylation of phosphatase and tensin homologue protein and poor prognosis. Min, Y.H., Cheong, J.W., Lee, M.H., Kim, J.Y., Lee, S.T., Hahn, J.S., Ko, Y.W. Clin. Cancer Res. (2004) [Pubmed]
  21. High expression of skp2 correlates with poor prognosis in endometrial endometrioid adenocarcinoma. Kamata, Y., Watanabe, J., Nishimura, Y., Arai, T., Kawaguchi, M., Hattori, M., Obokata, A., Kuramoto, H. J. Cancer Res. Clin. Oncol. (2005) [Pubmed]
  22. Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase. Takeda, D.Y., Parvin, J.D., Dutta, A. J. Biol. Chem. (2005) [Pubmed]
  23. Retinoic acid-mediated growth arrest requires ubiquitylation and degradation of the F-box protein Skp2. Dow, R., Hendley, J., Pirkmaier, A., Musgrove, E.A., Germain, D. J. Biol. Chem. (2001) [Pubmed]
  24. Identification of a novel Skp2-like mammalian protein containing F-box and leucine-rich repeats. Ilyin, G.P., Rialland, M., Glaise, D., Guguen-Guillouzo, C. FEBS Lett. (1999) [Pubmed]
  25. Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. Yang, E.S., Burnstein, K.L. J. Biol. Chem. (2003) [Pubmed]
  26. Characterization of the cullin and F-box protein partner Skp1. Ng, R.W., Arooz, T., Yam, C.H., Chan, I.W., Lau, A.W., Poon, R.Y. FEBS Lett. (1998) [Pubmed]
  27. The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclin E and regulates ubiquitin-dependent degradation of cyclin E. Yeh, K.H., Kondo, T., Zheng, J., Tsvetkov, L.M., Blair, J., Zhang, H. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  28. Three different binding sites of Cks1 are required for p27-ubiquitin ligation. Sitry, D., Seeliger, M.A., Ko, T.K., Ganoth, D., Breward, S.E., Itzhaki, L.S., Pagano, M., Hershko, A. J. Biol. Chem. (2002) [Pubmed]
  29. The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. Li, X., Zhao, Q., Liao, R., Sun, P., Wu, X. J. Biol. Chem. (2003) [Pubmed]
  30. E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Salon, C., Merdzhanova, G., Brambilla, C., Brambilla, E., Gazzeri, S., Eymin, B. Oncogene (2007) [Pubmed]
  31. Skp2 induction and phosphorylation is associated with the late G1 phase of proliferating rat hepatocytes. Bilodeau, M., Talarmin, H., Ilyin, G., Rescan, C., Glaise, D., Cariou, S., Loyer, P., Guguen-Guillouzo, C., Baffet, G. FEBS Lett. (1999) [Pubmed]
  32. Selective inhibition of cyclooxygenase 2 induces p27kip1 and skp2 in oral squamous cell carcinoma. Mäkitie, A.A., Chau, M., Lim, S., Viani, M.A., Gilbert, R., Lim, M.S., Jordan, R.C. The Journal of otolaryngology. (2003) [Pubmed]
  33. The X protein of hepatitis B virus binds to the F box protein Skp2 and inhibits the ubiquitination and proteasomal degradation of c-Myc. Kalra, N., Kumar, V. FEBS Lett. (2006) [Pubmed]
  34. Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. Bhatt, K.V., Hu, R., Spofford, L.S., Aplin, A.E. Oncogene (2007) [Pubmed]
  35. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Carrano, A.C., Eytan, E., Hershko, A., Pagano, M. Nat. Cell Biol. (1999) [Pubmed]
  36. Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2. Yam, C.H., Ng, R.W., Siu, W.Y., Lau, A.W., Poon, R.Y. Mol. Cell. Biol. (1999) [Pubmed]
  37. Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome. Bondar, T., Kalinina, A., Khair, L., Kopanja, D., Nag, A., Bagchi, S., Raychaudhuri, P. Mol. Cell. Biol. (2006) [Pubmed]
  38. Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. Foster, J.S., Fernando, R.I., Ishida, N., Nakayama, K.I., Wimalasena, J. J. Biol. Chem. (2003) [Pubmed]
  39. Prognostic impact of Skp2 and p27 in human breast cancer. Traub, F., Mengel, M., Lück, H.J., Kreipe, H.H., von Wasielewski, R. Breast Cancer Res. Treat. (2006) [Pubmed]
  40. Basic investigation on the development of molecular targeting therapy against cyclin-dependent kinase inhibitor p27Kip1 in head and neck cancer cells. Supriatno, n.u.l.l., Harada, K., Yoshida, H., Sato, M. Int. J. Oncol. (2005) [Pubmed]
  41. S-phase kinase-associated protein 2 expression in non-Hodgkin's lymphoma inversely correlates with p27 expression and defines cells in S phase. Chiarle, R., Fan, Y., Piva, R., Boggino, H., Skolnik, J., Novero, D., Palestro, G., De Wolf-Peeters, C., Chilosi, M., Pagano, M., Inghirami, G. Am. J. Pathol. (2002) [Pubmed]
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