Cell cycle - Role of SCF complex in cell cycle regulation

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Role of SCF complex in cell cycle regulation

The events controlling cell division are governed by the degradation of different regulatory proteins by the Ubiquitin-dependent pathway. Ubiquitin, a small protein of 76 amino acids is found in all eukaryotic cells. In the Ubiquitin-dependent pathway, the attachment of a polyubiquitin chain to a substrate is realized by an ubiquitin-ligase targets this substrate for degradation by the 26S proteasome. The ubiquitination pathway sequentially involves the E1 Ub-activating enzyme, E2 Ub-conjugating enzymes, and E3 Ub-ligases [1].

E1 Ub-activating enzyme (e.g. ubiquitin-activating enzyme E1 (UBE1)) activates Ubiquitin in the ATP-dependent manner [2] and transfers it to E2 Ub-conjugating enzyme through thioester bond formation. E2 Ub-conjugating enzyme (e.g. cell division cycle 34 ubiquitin-protein ligase (CDC34)) activates ubiquitin-polymerization [3]. E3 Ub-ligase mediates the transfer of Ubiquitin from E2 Ub-conjugating enzyme to the substrate protein [1].

S-phase kinase-associated protein 1 p19 (SKP1)/ Cullin/F-box complex (SCF complex) is one of E3-ubiquitin ligases, which play a very important role in the cell cycle. SCF complex consists of Cullin 1, SKP1, F-box proteins (e.g. S-phase kinase-associated protein 2 p45 (Skp2), beta-transducin repeat containing protein (TrCP) or F-box protein FBW7 (FBXW7)) and RING-box protein 1. The Cullin 1/ RING-box protein 1 components are associated with E2 Ub-conjugating enzymes [1]. Ubiquitin-lake protein NEDD8 charged surface residues mediates activation of Cullin 1 / RING-box protein 1, which is needed to specifically support Cdc34-catalyzed ubiquitin polymerization [3]. F-box proteins directly recruit ubiquitination substrates and bridge the interaction between E2 Ub-conjugating enzyme and the substrate [1].

SCF complex participates in cell cycle regulation by stimulating ubiquitination of the cell cycle proteins and their degradation by the 26S proteasome. Most substrates require phosphorylation to interact with the F-box protein in an SCF complex [1].

Cell division cycle 25A phosphotase (CDC25A), Cyclin D, Cyclin E, cyclin-dependent kinase 2 (CDK2), DNA replication factor (Cdt1), cyclin-dependent kinase inhibitor 1A (p21), cyclin-dependent kinase inhibitor 1B (p27KIP1), E2F transcription factor 1 (E2F1) and retinoblastoma-like 2 (p130) bind to SCF complex and degrade during interphase [1], [4].

CDC25A is phosphorylated by some kinases in response to DNA damage (e.g. cell cycle checkpoint kinase 1 (Chk1). Phosphorylated CDC25A is ubiquitinated by SCF complex in late S and G2 phases [5]. Stimulation of the growth factor beta (TGF-beta)/ SMAD family member 3 (Smad3) pathway promotes SCF complex-mediated CDC25A ubiquitination [6]. Moreover, SCF complex may promote ubiquitin-proteasome degradation of Smad3 [7].

Phosphorylated by cyclin-dependent kinases (e.g. cyclin-dependent kinase 4 (CDK4)) p130 is ubiquitinated by SCF complex in G1 phase [8].

CDK2 binds to SCF complex and is degraded during late S or G2 phase. At the same time, phosphorylation of p27KIP1 [9], Cyclin E [10] and Cdt1 [11] by CDK2 promotes their SCF complex-mediated destruction during G1 and S phases [1]. Ubiquitination of p27KIP1 requires the SCF complex and Skp2 F-box binding protein CKS1 [12]. SKP2 and CKS1 are negatively regulated by Anaphase-promoting/ cell division cycle 20 related 1 protein complex (APC/hCdh1)-mediated ubiquitination. Targeting of SKP2 and CKS1 by APC/hCdh1 stabilizes p27KIP1, subsequently leading to the maintenance of G1 phase and blocking premature S-phase initiation [13], [14].

Cyclin D1 [15] and p21 bind to the SCF complex and get degraded during interphase too [16].

Tyrosine kinase Wee1 and F-box protein 5 (Emi1) bind to SCF complex and degrade during mitosis.

Major M-phase kinases Polo-like kinase 1 (Plk1) and Cdk1 phosphorylate WEE1 [17] and Emi1 [18], [19]. The phosphorylation makes WEE1 and Emi1 accessible to SCF complex-mediated degradation. Emi1 promotes S phase entry in somatic cells by inhibiting the APC/hCdh1 complex [20].

References:

  1. Ang XL, Wade Harper J
    SCF-mediated protein degradation and cell cycle control. Oncogene 2005 Apr 18;24(17):2860-70
  2. Handley PM, Mueckler M, Siegel NR, Ciechanover A, Schwartz AL
    Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1. Proceedings of the National Academy of Sciences of the United States of America 1991 Jan 1;88(1):258-62
  3. Wu K, Chen A, Tan P, Pan ZQ
    The Nedd8-conjugated ROC1-CUL1 core ubiquitin ligase utilizes Nedd8 charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34. The Journal of biological chemistry 2002 Jan 4;277(1):516-27
  4. Ohta T, Xiong Y
    Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases. Cancer research 2001 Feb 15;61(4):1347-53
  5. Busino L, Chiesa M, Draetta GF, Donzelli M
    Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 2004 Mar 15;23(11):2050-6
  6. Ray D, Terao Y, Nimbalkar D, Chu LH, Donzelli M, Tsutsui T, Zou X, Ghosh AK, Varga J, Draetta GF, Kiyokawa H
    Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Molecular and cellular biology 2005 Apr;25(8):3338-47
  7. Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K
    Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Molecular biology of the cell 2001 May;12(5):1431-43
  8. Bhattacharya S, Garriga J, Calbo J, Yong T, Haines DS, Gra?a X
    SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 2003 Apr 24;22(16):2443-51
  9. Carrano AC, Eytan E, Hershko A, Pagano M
    SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nature cell biology 1999 Aug;1(4):193-9
  10. Yeh KH, Kondo T, Zheng J, Tsvetkov LM, Blair J, Zhang H
    The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclin E and regulates ubiquitin-dependent degradation of cyclin E. Biochemical and biophysical research communications 2001 Mar 9;281(4):884-90
  11. Nishitani H, Taraviras S, Lygerou Z, Nishimoto T
    The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase. The Journal of biological chemistry 2001 Nov 30;276(48):44905-11
  12. Wang W, Ungermannova D, Chen L, Liu X
    A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1. The Journal of biological chemistry 2003 Aug 22;278(34):32390-6
  13. Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M
    Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 2004 Mar 11;428(6979):190-3
  14. Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr
    Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 2004 Mar 11;428(6979):194-8
  15. Maeda I, Ohta T, Koizumi H, Fukuda M
    In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS letters 2001 Apr 13;494(3):181-5
  16. Yam CH, Ng RW, Siu WY, Lau AW, Poon RY
    Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2. Molecular and cellular biology 1999 Jan;19(1):635-45
  17. Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H
    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 2004 Mar 30;101(13):4419-24
  18. Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK
    Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Developmental cell 2003 Jun;4(6):813-26
  19. Moshe Y, Boulaire J, Pagano M, Hershko A
    Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proceedings of the National Academy of Sciences of the United States of America 2004 May 25;101(21):7937-42
  20. Hsu JY, Reimann JD, S?rensen CS, Lukas J, Jackson PK
    E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nature cell biology 2002 May;4(5):358-66

  1. Ang XL, Wade Harper J
    SCF-mediated protein degradation and cell cycle control. Oncogene 2005 Apr 18;24(17):2860-70
  2. Handley PM, Mueckler M, Siegel NR, Ciechanover A, Schwartz AL
    Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1. Proceedings of the National Academy of Sciences of the United States of America 1991 Jan 1;88(1):258-62
  3. Wu K, Chen A, Tan P, Pan ZQ
    The Nedd8-conjugated ROC1-CUL1 core ubiquitin ligase utilizes Nedd8 charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34. The Journal of biological chemistry 2002 Jan 4;277(1):516-27
  4. Ohta T, Xiong Y
    Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases. Cancer research 2001 Feb 15;61(4):1347-53
  5. Busino L, Chiesa M, Draetta GF, Donzelli M
    Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 2004 Mar 15;23(11):2050-6
  6. Ray D, Terao Y, Nimbalkar D, Chu LH, Donzelli M, Tsutsui T, Zou X, Ghosh AK, Varga J, Draetta GF, Kiyokawa H
    Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Molecular and cellular biology 2005 Apr;25(8):3338-47
  7. Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K
    Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Molecular biology of the cell 2001 May;12(5):1431-43
  8. Bhattacharya S, Garriga J, Calbo J, Yong T, Haines DS, Gra?a X
    SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 2003 Apr 24;22(16):2443-51
  9. Carrano AC, Eytan E, Hershko A, Pagano M
    SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nature cell biology 1999 Aug;1(4):193-9
  10. Yeh KH, Kondo T, Zheng J, Tsvetkov LM, Blair J, Zhang H
    The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclin E and regulates ubiquitin-dependent degradation of cyclin E. Biochemical and biophysical research communications 2001 Mar 9;281(4):884-90
  11. Nishitani H, Taraviras S, Lygerou Z, Nishimoto T
    The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase. The Journal of biological chemistry 2001 Nov 30;276(48):44905-11
  12. Wang W, Ungermannova D, Chen L, Liu X
    A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1. The Journal of biological chemistry 2003 Aug 22;278(34):32390-6
  13. Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M
    Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 2004 Mar 11;428(6979):190-3
  14. Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr
    Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 2004 Mar 11;428(6979):194-8
  15. Maeda I, Ohta T, Koizumi H, Fukuda M
    In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS letters 2001 Apr 13;494(3):181-5
  16. Yam CH, Ng RW, Siu WY, Lau AW, Poon RY
    Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2. Molecular and cellular biology 1999 Jan;19(1):635-45
  17. Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T, Osada H
    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 2004 Mar 30;101(13):4419-24
  18. Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK
    Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Developmental cell 2003 Jun;4(6):813-26
  19. Moshe Y, Boulaire J, Pagano M, Hershko A
    Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proceedings of the National Academy of Sciences of the United States of America 2004 May 25;101(21):7937-42
  20. Hsu JY, Reimann JD, S?rensen CS, Lukas J, Jackson PK
    E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nature cell biology 2002 May;4(5):358-66

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