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Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.
Ng VH, Hang BI, Sawyer LM, Neitzel LR, Crispi EE, Rose KL, Popay TM, Zhong A, Lee LA, Tansey WP, Huppert S, Lee E
(2018) J Cell Sci 131:
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Cell Line, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins, Phosphorylation, Protein Binding, Threonine, Wnt Signaling Pathway, Wnt3A Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus
Show Abstract · Added July 6, 2018
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in embryos. Although XIAP ubiquitylates TLE3 at wild-type levels , it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.
© 2018. Published by The Company of Biologists Ltd.
0 Communities
2 Members
0 Resources
15 MeSH Terms
XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling.
Hanson AJ, Wallace HA, Freeman TJ, Beauchamp RD, Lee LA, Lee E
(2012) Mol Cell 45: 619-28
MeSH Terms: Animals, Co-Repressor Proteins, Drosophila, Drosophila Proteins, Embryo, Nonmammalian, HEK293 Cells, Humans, Inhibitor of Apoptosis Proteins, Models, Genetic, RNA Interference, Ubiquitination, Wnt Proteins, Wnt Signaling Pathway, Wnt1 Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus, Xenopus Proteins
Show Abstract · Added June 14, 2013
A key event in Wnt signaling is conversion of TCF/Lef from a transcriptional repressor to an activator, yet how this switch occurs is not well understood. Here, we report an unanticipated role for X-linked inhibitor of apoptosis (XIAP) in regulating this critical Wnt signaling event that is independent of its antiapoptotic function. We identified DIAP1 as a positive regulator of Wingless signaling in a Drosophila S2 cell-based RNAi screen. XIAP, its vertebrate homolog, is similarly required for Wnt signaling in cultured mammalian cells and in Xenopus embryos, indicating evolutionary conservation of function. Upon Wnt pathway activation, XIAP is recruited to TCF/Lef where it monoubiquitylates Groucho (Gro)/TLE. This modification decreases affinity of Gro/TLE for TCF/Lef. Our data reveal a transcriptional switch involving XIAP-mediated ubiquitylation of Gro/TLE that facilitates its removal from TCF/Lef, thus allowing β-catenin-TCF/Lef complex assembly and initiation of a Wnt-specific transcriptional program.
Copyright © 2012 Elsevier Inc. All rights reserved.
2 Communities
4 Members
0 Resources
17 MeSH Terms
S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2.
Ghavami S, Kerkhoff C, Chazin WJ, Kadkhoda K, Xiao W, Zuse A, Hashemi M, Eshraghi M, Schulze-Osthoff K, Klonisch T, Los M
(2008) Biochim Biophys Acta 1783: 297-311
MeSH Terms: Animals, Apoptosis Regulatory Proteins, Calgranulin A, Calgranulin B, Cell Death, Cell Line, Tumor, Down-Regulation, Dynamins, Fas-Associated Death Domain Protein, High-Temperature Requirement A Serine Peptidase 2, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mitochondria, Mitochondrial Proteins, Protein Binding, Protein Processing, Post-Translational, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Serine Endopeptidases, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Show Abstract · Added May 19, 2014
A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (DeltaPsi(m)) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-X(L), whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.
0 Communities
1 Members
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23 MeSH Terms
Non-peptidic small molecule inhibitors of XIAP.
Park CM, Sun C, Olejniczak ET, Wilson AE, Meadows RP, Betz SF, Elmore SW, Fesik SW
(2005) Bioorg Med Chem Lett 15: 771-5
MeSH Terms: Binding Sites, Drug Design, Heterocyclic Compounds, Humans, Imidazoles, Ligands, Magnetic Resonance Spectroscopy, Proteins, Structure-Activity Relationship, Thiazoles, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
Non-peptidic small molecule SMAC mimetics were designed and synthesized that bind to the BIR3 domain of XIAP using structure-based design. Substituted five-membered heterocycles such as thiazoles and imidazoles were identified that serve as replacements for peptide fragments of the lead.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.
Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW
(2004) J Med Chem 47: 4417-26
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Binding Sites, Breast Neoplasms, Carrier Proteins, Caspases, Cell Division, Cell Line, Tumor, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Mice, Mitochondrial Proteins, Peptide Fragments, Protein Structure, Tertiary, Proteins, Structure-Activity Relationship, Transplantation, Heterologous, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Regulation of the Apaf-1/caspase-9 apoptosome by caspase-3 and XIAP.
Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC
(2003) J Biol Chem 278: 8091-8
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, Caspase 3, Caspase 9, Caspase Inhibitors, Caspases, Cytochrome c Group, Enzyme Activation, Humans, Hydrolysis, Kinetics, Molecular Sequence Data, Proteins, Recombinant Proteins, Sequence Homology, Amino Acid, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The apoptosome is a multiprotein complex comprising Apaf-1, cytochrome c, and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response to apoptotic signals. Binding of cytochrome c and dATP to Apaf-1 in the cytosol leads to the assembly of a heptameric complex in which each Apaf-1 subunit is bound noncovalently to a procaspase-9 subunit via their respective CARD domains. Assembly of the apoptosome results in the proteolytic cleavage of procaspase-9 at the cleavage site PEPD(315) to yield the large (p35) and small (p12) caspase-9 subunits. In addition to the PEPD site, caspase-9 contains a caspase-3 cleavage site (DQLD(330)), which when cleaved, produces a smaller p10 subunit in which the NH(2)-terminal 15 amino acids of p12, including the XIAP BIR3 binding motif, are removed. Using purified proteins in a reconstituted reaction in vitro, we have assessed the relative impact of Asp(315) and Asp(330) cleavage on caspase-9 activity within the apoptosome. In addition, we characterized the effect of caspase-3 feedback cleavage of caspase-9 on the rate of caspase-3 activation, and the potential ramifications of Asp(330) cleavage on XIAP-mediated inhibition of the apoptosome. We have found that cleavage of procaspase-9 at Asp(330) to generate p35, p10 or p37, p10 forms resulted in a significant increase (up to 8-fold) in apoptosome activity compared with p35/p12. The significance of this increase was demonstrated by the near complete loss of apoptosome-mediated caspase-3 activity when a point mutant (D330A) of procaspase-9 was substituted for wild-type procaspase-9 in the apoptosome. In addition, cleavage at Asp(330) exposed a novel p10 NH(2)-terminal peptide motif (AISS) that retained the ability to mediate XIAP inhibition of caspase-9. Thus, whereas feedback cleavage of caspase-9 by caspase-3 significantly increases the activity of the apoptosome, it does little to attenuate its sensitivity to inhibition by XIAP.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Structural biology. Controlling the caspases.
Fesik SW, Shi Y
(2001) Science 294: 1477-8
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis, Apoptosis Regulatory Proteins, Binding Sites, Carrier Proteins, Caspase Inhibitors, Caspases, Crystallography, X-Ray, Cysteine Proteinase Inhibitors, Dimerization, Humans, Hydrogen Bonding, Intracellular Signaling Peptides and Proteins, Mitochondria, Mitochondrial Proteins, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, X-Linked Inhibitor of Apoptosis Protein
Added March 5, 2014
0 Communities
1 Members
0 Resources
20 MeSH Terms
Structural basis for the inhibition of caspase-3 by XIAP.
Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS
(2001) Cell 104: 791-800
MeSH Terms: Carrier Proteins, Caspase 3, Caspases, Catalytic Domain, Crystallography, Mitochondrial Proteins, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, Structure-Activity Relationship, Substrate Specificity, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.
Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW
(2000) Nature 408: 1004-8
MeSH Terms: Amino Acid Sequence, Antineoplastic Agents, Apoptosis Regulatory Proteins, Binding Sites, Carrier Proteins, Caspase 9, Caspase Inhibitors, Cloning, Molecular, Cysteine Proteinase Inhibitors, Escherichia coli, Humans, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Spectroscopy, Mitochondrial Proteins, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Tertiary, Proteins, Sequence Homology, Amino Acid, Structure-Activity Relationship, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third beta-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.
0 Communities
1 Members
0 Resources
23 MeSH Terms
NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP.
Sun C, Cai M, Meadows RP, Xu N, Gunasekera AH, Herrmann J, Wu JC, Fesik SW
(2000) J Biol Chem 275: 33777-81
MeSH Terms: Amino Acid Sequence, Apoptosis, Caspase 9, Caspase Inhibitors, Enzyme Inhibitors, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Structure, Secondary, Proteins, Repetitive Sequences, Amino Acid, Structure-Activity Relationship, X-Linked Inhibitor of Apoptosis Protein
Show Abstract · Added March 5, 2014
The inhibitor of apoptosis proteins (IAPs) regulate the caspase family of cysteine proteases, which play an important role in the execution of programmed cell death. Human X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases-3, -7, and -9. Here we show that the Bir3 domain is the minimal region of XIAP that is needed for potent caspase-9 inhibition. The three-dimensional structure of the Bir3 domain of XIAP, determined by NMR spectroscopy, resembles a classical zinc finger and consists of five alpha-helices, a three-stranded beta-sheet, and a zinc atom chelated to three cysteines and one histidine. The structure of the Bir3 domain is similar to that of the Bir2 domain of XIAP but differs from the previously determined structure of the Bir3 domain of MIHB. Based on site-directed mutagenesis, we have identified the regions of the Bir3 domain of XIAP that are important for inhibiting caspase-9. Despite the structural similarities of the Bir2 and Bir3 domain of XIAP, a different set of residues were found to be critical for inhibiting the individual caspases. These results suggest that XIAP inhibits caspase-3 and caspase-9 in a different manner.
0 Communities
1 Members
0 Resources
13 MeSH Terms