Desumoylation Activity of Axam, a Novel Axin-Binding Protein, Is Involved in Downregulation of β-Catenin

Kadoya, Takayuki; Yamamoto, Hideki; Suzuki, Toshiaki; Yukita, Akira; Fukui, Akimasa; Michiue, Tatsuo; Asahara, Toshimasa; Tanaka, Keiji; Asashima, Makoto; Kikuchi, Akira

doi:10.1128/mcb.22.11.3803-3819.2002

Cited by 68 publications

(74 citation statements)

References 70 publications

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“…The catalytic activity of Axam is required for its down-regulation of ␤-catenin (43,50). This is consistent with the observation that sumoylation represses LEF1 activity (29).…”

Section: Pias-mediated Jnk Activation Is Blocked By Dominant Negativesupporting

confidence: 76%

SUMO-1 Modification of the C-terminal KVEKVD of Axin Is Required for JNK Activation but Has No Effect on Wnt Signaling

Rui

Fan

Zhou

et al. 2002

Journal of Biological Chemistry

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Axin is a multifunctional protein, regulating Wnt signaling and the c-Jun N-terminal/stress-activated protein kinase (JNK/SAPK) pathway as well as tumorigenesis. In the present study, we found that Axin interacts with three SUMO-1 (small ubiquitin-related modifier) conjugating enzymes 3 (E3), PIAS1, PIASx␤, and PIASy. The extreme C-terminal six amino acid residues of Axin are critical for the Axin/E3 interaction as deletion of the six residues (Axin⌬C6) completely abolished the ability of Axin to interact with E3 enzymes. Axin⌬C6 also failed to activate JNK, although it was intact in both its interaction with MEKK1 and homodimerization. Consistent with the presence of a doublet of the KV(E/D) sumoylation consensus motif at the C-terminal end (KVEKVD), we found that Axin is heavily sumoylated. Deletion of the C-terminal six amino acids drastically reduced sumoylation, indicating that the C-terminal six amino acids stretch is the main sumoylation site for Axin. Sumoylation-defective mutants failed to activate JNK but effectively destabilized ␤-catenin and attenuated LEF1 transcriptional activity. In addition, we show that dominant negative Axin mutants blocked PIAS-mediated JNK activation, in accordance with the requirement of sumoylation for Axin-mediated JNK activation.Taken together, we demonstrate that sumoylation plays a role for Axin to function in the JNK pathway.

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“…The catalytic activity of Axam is required for its down-regulation of ␤-catenin (43,50). This is consistent with the observation that sumoylation represses LEF1 activity (29).…”

Section: Pias-mediated Jnk Activation Is Blocked By Dominant Negativesupporting

confidence: 76%

SUMO-1 Modification of the C-terminal KVEKVD of Axin Is Required for JNK Activation but Has No Effect on Wnt Signaling

Rui

Fan

Zhou

et al. 2002

Journal of Biological Chemistry

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“…5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions. 5,6,[8][9][10][11][12] However, it is not known how these SUMO-specific proteases are regulated.HIPK1 is one of three closely related serine/threonine protein kinases that are primarily localized in the nucleus where it is sumoylated. 13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors.…”

mentioning

confidence: 99%

“…4 Several members of SUMOspecific proteases have been reported in the mammalian system. [5][6][7][8][9][10] SENP1 is a protease that appears to deconjugate a large number of sumoylated proteins. 5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions.…”

mentioning

confidence: 99%

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SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Luo

et al. 2008

Cell Death Differ

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We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalyticinactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis. The small ubiquitin-like modifier (SUMO) can be covalently attached to a large number of proteins through the formation of isopeptide bonds with specific lysine residues of target proteins. 1,2 A large number of sumoylated proteins, including RanGAP1, PML, homeodomain-interacting protein kinases (HIPKs), IkB, p53, c-Jun, Sp3, Elk-1, p300 histone acetyltransferase, histone deacetylase (HDAC), and many nuclear receptors, have been identified. 1-3 Sumoylation is a dynamic process that is mediated by activating, conjugating, and ligating enzymes and that is readily reversed by a family of SUMO-specific proteases. 4 Several members of SUMOspecific proteases have been reported in the mammalian system. 5-10 SENP1 is a protease that appears to deconjugate a large number of sumoylated proteins. 5 Different members of these SUMO-specific proteases appear to localize in different cellular compartments where they regulate protein function by modifying the protein stability, cellular localization, and protein-protein interactions. 5,6,[8][9][10][11][12] However, it is not known how these SUMO-specific proteases are regulated.HIPK1 is one of three closely related serine/threonine protein kinases that are primarily localized in the nucleus where it is sumoylated. 13,14 The HIPKs were originally identified as nuclear protein kinases that function as co-repressors for various homeodomain-containing transcription factors. 15 Recently, HIPKs have been shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. In nucleus, HIPK2 phosphorylates p53 on Ser 46, resulting in the activatio...

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“…Sumoylation is a dynamic and reversible process (34,(41)(42)(43). SUMOspecific proteases (SENPs) responsible for desumoylation have been identified from yeast to mammals (32,(41)(42)(43)(44)(45)(46)(47). Although several SENPs have been reported in mammals (32,39,41,45,48), the biological function of SENPs remains to be characterized.…”

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confidence: 99%

Differential Regulation of c-Jun-dependent Transcription by SUMO-specific Proteases

Cheng

Perkins

Yeh

2005

Journal of Biological Chemistry

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c-Jun is a transcription factor that plays an important role in regulating cell growth, apoptosis, differentiation, and transformation. The transcriptional activity of c-Jun can be regulated by both phosphorylation and sumoylation. It has also been shown that c-Jun transcription can be regulated by SuPr-1, an alternatively spliced form of SUMO-specific protease 2 (SENP2). However, the ability of SuPr-1 to enhance c-Jun transcription is dependent on promyelocytic leukemia but is independent of the desumoylation activity of SuPr-1. Here, we show that SUMOspecific protease 1 (SENP1) also markedly enhances the transcription activity of c-Jun. The action of SENP1 on c-Jun transcription is independent of the sumoylation and phosphorylation status of c-Jun but is critically dependent on the desumoylation activity of SENP1. We further show that p300 is essential for SENP1 to enhance c-Jun-dependent transcription because SENP1 can desumoylate the CRD1 domain of p300, thereby releasing the cis-repression of CRD1 on p300. Thus, two SUMO-specific proteases regulate c-Jun-dependent transcription through entirely different mechanisms.

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Desumoylation Activity of Axam, a Novel Axin-Binding Protein, Is Involved in Downregulation of β-Catenin

Abstract: Axam has been identified as a novel Axin-binding protein that inhibits the Wnt signaling pathway. We studied the molecular mechanism by which Axam stimulates the downregulation of ␤-catenin.

Cited by 68 publications

References 70 publications

SUMO-1 Modification of the C-terminal KVEKVD of Axin Is Required for JNK Activation but Has No Effect on Wnt Signaling

SUMO-1 Modification of the C-terminal KVEKVD of Axin Is Required for JNK Activation but Has No Effect on Wnt Signaling

SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis

Differential Regulation of c-Jun-dependent Transcription by SUMO-specific Proteases

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