Pathway maps

Proteolysis_Putative SUMO-1 pathway
Proteolysis_Putative SUMO-1 pathway

Object List (links open in MetaCore):

c-Jun, P53, RanGAP1, Pc2, SAE1, MDM2, TOP2, UBE2E3, GCR-alpha, PIAS1, DAXX, c-Myb, ATP, SP3, E2I, NF-kB, PML, SENP1, HSF2, SP100, SUMO-1, Ubiquitin, SAE1/2, SAE2, RanBP2, HSF1, FasR(CD95), PIAS2, NFKBIA

Description

Putative SUMO-1 pathway

Sumoylation is a multi-step protein modification reaction. It implicates Small ubiquitin-like modifier (SUMO) proteins, such as SMT3 suppressor of mif two 3 homolog 1 ( SUMO-1 ). These proteins get attached covalently to lysine residues of substrate/target proteins. As a result, in contrast to ubiquitination that targets proteins for degradation, activities of the sumoylated proteins get modulated to affect a number of biological functions, including control of gene expression, maintenance of genome integrity, intracellular transport and protein stability [1], [2].

Attachment of SUMO-1 to substrate proteins is carried out by enzymatic cascade involving SUMO-activating enzyme (E1), SUMO-conjugating enzyme (E2) and SUMO protein ligase (E3). A group of proteases known as SENPs are involved in both the maturation of SUMO precursors (endopeptidase cleavage) and deconjugation of the targets (isopeptidase cleavage).

SUMO-1 is processed by SUMO1/sentrin specific peptidase 1 ( SENP1 ) (endopeptidase cleavage) before being activated. Processed SUMO-1, in the ATP-dependent manner, is covalently linked to the SUMO E1-activating enzyme complex ( SAE1/2 ) composed of two catalytically active subunits, SUMO1 activating enzyme subunit 1 ( SAE1 ) and Ubiquitin-like modifier activating enzyme 2 ( SAE2 ). SUMO-1 is then transferred to the SUMO E2-conjugating enzymes, such as Ubiquitin-conjugating enzyme E2I ( E2I ) and Ubiquitin-conjugating enzyme E2E 3 ( UBE2E3 ), that mediate target protein modification by SUMO E3 ligases, such as RAN binding protein 2 ( RanBP2 ), Chromobox homolog 4 ( Pc2 ) and specific E3-like ligases PIAS1 and PIAS2 ( Protein inhibitors of activated STAT, 1 and 2) [3], [4], [5], [6], [1]. Cleavage of the SUMO-1 from the target protein is mediated by SENP1 peptidase (isopeptidase cleavage) [1].

Mdm2 p53 binding protein homolog ( MDM2 ) is an ubiquitin ligase (E3) that acts on Tumor protein p53 ( p53 ). It attaches Ubiquitin to p53 leading to proteasomal degradation of the latter [7]. E3 ligase RanBP2 is a nuclear pore protein and E3 ligases PIAS1 and PIAS2 are localized within the nucleus. MDM2 is sumoylated during nuclear translocation by RanBP2, and then sumoylated again in the nucleus by PIAS1 and PIAS2 [8].

PIAS1 and PIAS2 also promote sumoylation of several transcription factors, such as p53, c-Jun and SP3. This modification modulates their transcriptional activity, e.g., SUMO-1 modification silences SP3 activity [4], [9].

Sumoylation is involved in both the direct regulation of p53 protein stability and function via direct modification of p53, and indirect modulation of the stability of MDM2. Although, the functional consequence of direct SUMO-1 modification of p53 is under debate, it is generally believed that sumoylation represses activity of this transcription factor. The indirect process has to do with, the turnover rate of p53 being related to E3 ubiquitin ligase activity of MDM2, the latter itself being a target of sumoylation. SUMO-1 -modified MDM2 cannot be ubiquitinated as efficiently as the free MDM2. Thereby, SUMO-1 -modified MDM2 exhibits reduced self-ubiquitination which leads to an accumulation of MDM2. Since p53 is a target of MDM2 E3 ubiquitin ligase activity, the p53 levels stay low in the presence of SUMO-1 -modified MDM2 [4], [6].

RanBP2 promotes sumoylation of Ran GTPase activating protein 1 ( RanGAP1 ), stimulates RanGAP1 functions and increases the accumulation of properly folded RanGAP1 protein [10], [11], [12].

Activation of Nuclear factor NF-kappa-B ( NF-kB ) is achieved by ubiquitination and proteasome-mediated degradation of inhibitory I-kappa-B proteins ( NFKBIA or NFKBIB). The latter inactivate NF-kB by trapping it in the cytoplasm. NFKBIA, conjugated to SUMO-1, is resistant to ubiquitin-induced degradation. Thus, NFKBIA sumoylation inhibits signal-induced activation of NF-kB -dependent transcription [13].

The sumoylation of TNF receptor superfamily member 6 ( FasR(CD95) ), v-Myb myeloblastosis viral oncogene homolog ( c-Myb ), Promyelocytic leukemia protein ( PML ), Heat shock transcription factor 1 ( HSF1 ), Heat shock transcription factor 2 ( HSF2 ), Glucocorticoid receptor ( GCR-alpha ), Nuclear antigen SP100 ( SP100 ), Death-domain associated protein ( DAXX ), and DNA topoisomerase II ( TOP2 ) regulates subcellular localization, stability and functional activity of these proteins [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30].

References:

  1. Hay RT
    SUMO-specific proteases: a twist in the tail. Trends in cell biology 2007 Aug;17(8):370-6
  2. Tang Z, Hecker CM, Scheschonka A, Betz H
    Protein interactions in the sumoylation cascade: lessons from X-ray structures. The FEBS journal 2008 Jun;275(12):3003-15
  3. Desterro JM, Rodriguez MS, Kemp GD, Hay RT
    Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. The Journal of biological chemistry 1999 Apr 9;274(15):10618-24
  4. Schmidt D, Muller S
    Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proceedings of the National Academy of Sciences of the United States of America 2002 Mar 5;99(5):2872-7
  5. Okubo S, Hara F, Tsuchida Y, Shimotakahara S, Suzuki S, Hatanaka H, Yokoyama S, Tanaka H, Yasuda H, Shindo H
    NMR structure of the N-terminal domain of SUMO ligase PIAS1 and its interaction with tumor suppressor p53 and A/T-rich DNA oligomers. The Journal of biological chemistry 2004 Jul 23;279(30):31455-61
  6. Kim KI, Baek SH
    SUMOylation code in cancer development and metastasis. Molecules and cells 2006 Dec 31;22(3):247-53
  7. Kubbutat MH, Jones SN, Vousden KH
    Regulation of p53 stability by Mdm2. Nature 1997 May 15;387(6630):299-303
  8. Miyauchi Y, Yogosawa S, Honda R, Nishida T, Yasuda H
    Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes. The Journal of biological chemistry 2002 Dec 20;277(51):50131-6
  9. Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, Suske G
    Transcription factor Sp3 is silenced through SUMO modification by PIAS1. The EMBO journal 2002 Oct 1;21(19):5206-15
  10. Joseph J, Tan SH, Karpova TS, McNally JG, Dasso M
    SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. The Journal of cell biology 2002 Feb 18;156(4):595-602
  11. Zhang H, Saitoh H, Matunis MJ
    Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Molecular and cellular biology 2002 Sep;22(18):6498-508
  12. Yi H, Friedman JL, A Ferreira P
    The Cyclophilin-like Domain of Ran-binding Protein-2 Modulates Selectively the Activity of the Ubiquitin-Proteasome System and Protein Biogenesis. The Journal of biological chemistry 2007 Nov 30;282(48):34770-8
  13. Desterro JM, Rodriguez MS, Hay RT
    SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Molecular cell 1998 Aug;2(2):233-9
  14. Tsytsykova AV, Tsitsikov EN, Wright DA, Futcher B, Geha RS
    The mouse genome contains two expressed intronless retroposed pseudogenes for the sentrin/sumo-1/PIC1 conjugating enzyme Ubc9. Molecular immunology 1998 Nov;35(16):1057-67
  15. Mao Y, Desai SD, Liu LF
    SUMO-1 conjugation to human DNA topoisomerase II isozymes. The Journal of biological chemistry 2000 Aug 25;275(34):26066-73
  16. Ryu SW, Chae SK, Kim E
    Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9. Biochemical and biophysical research communications 2000 Dec 9;279(1):6-10
  17. Goodson ML, Hong Y, Rogers R, Matunis MJ, Park-Sarge OK, Sarge KD
    Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. The Journal of biological chemistry 2001 May 25;276(21):18513-8
  18. Seeler JS, Marchio A, Losson R, Desterro JM, Hay RT, Chambon P, Dejean A
    Common properties of nuclear body protein SP100 and TIF1alpha chromatin factor: role of SUMO modification. Molecular and cellular biology 2001 May;21(10):3314-24
  19. Hong Y, Rogers R, Matunis MJ, Mayhew CN, Goodson ML, Park-Sarge OK, Sarge KD
    Regulation of heat shock transcription factor 1 by stress-induced SUMO-1 modification. The Journal of biological chemistry 2001 Oct 26;276(43):40263-7
  20. Bies J, Markus J, Wolff L
    Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity. The Journal of biological chemistry 2002 Mar 15;277(11):8999-9009
  21. Jang MS, Ryu SW, Kim E
    Modification of Daxx by small ubiquitin-related modifier-1. Biochemical and biophysical research communications 2002 Jul 12;295(2):495-500
  22. Le Drean Y, Mincheneau N, Le Goff P, Michel D
    Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 2002 Sep;143(9):3482-9
  23. Verger A, Perdomo J, Crossley M
    Modification with SUMO. A role in transcriptional regulation. EMBO reports 2003 Feb;4(2):137-42
  24. Hietakangas V, Ahlskog JK, Jakobsson AM, Hellesuo M, Sahlberg NM, Holmberg CI, Mikhailov A, Palvimo JJ, Pirkkala L, Sistonen L
    Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Molecular and cellular biology 2003 Apr;23(8):2953-68
  25. Isik S, Sano K, Tsutsui K, Seki M, Enomoto T, Saitoh H
    The SUMO pathway is required for selective degradation of DNA topoisomerase IIbeta induced by a catalytic inhibitor ICRF-193(1). FEBS letters 2003 Jul 10;546(2-3):374-8
  26. Anckar J, Hietakangas V, Denessiouk K, Thiele DJ, Johnson MS, Sistonen L
    Inhibition of DNA binding by differential sumoylation of heat shock factors. Molecular and cellular biology 2006 Feb;26(3):955-64
  27. Chen A, Wang PY, Yang YC, Huang YH, Yeh JJ, Chou YH, Cheng JT, Hong YR, Li SS
    SUMO regulates the cytoplasmonuclear transport of its target protein Daxx. Journal of cellular biochemistry 2006 Jul 1;98(4):895-911
  28. Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP
    The Mechanisms of PML-Nuclear Body Formation. Molecular cell 2006 Nov 3;24(3):331-9
  29. Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Wille A, Drynda A, Mendoza H, Gay RE, Hay RT, Ink B, Gay S, Pap T
    Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 2007 Mar 14;
  30. Takahashi Y, Strunnikov A
    In vivo modeling of polysumoylation uncovers targeting of Topoisomerase II to the nucleolus via optimal level of SUMO modification. Chromosoma 2007 Nov 29;