Search results for IPPK

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Protein (2 results from a total of 2)

Identifier: R-HSA-1604598
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: IPPK: Q9H8X2
Identifier: R-HSA-2023949
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: Q9H8X2

Reaction (4 results from a total of 4)

Identifier: R-HSA-1855179
Species: Homo sapiens
Compartment: cytosol
Inositolpentakisphosphate 2-kinase (IPPK), also known as IP52K, phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbski et al. 2002, Brehm et al. 2007, Choi et al. 2007).
Identifier: R-HSA-1855176
Species: Homo sapiens
Compartment: nucleoplasm
In the nucleus, inositol-pentakisphosphate 2-kinase (IPPK - also known as IP5-2K) phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007).
Identifier: R-HSA-9687638
Species: Homo sapiens
Compartment: cytosol
Metabolites of the inositol phosphate (IP) pathway I(1,3,4,6)P4, I(1,3,4,5,6)P5, and IP6 promote membrane permeabilization mediated by the pseudokinase mixed lineage kinase domain-like (MLKL) through directly binding the N‑terminal four-helical bundle (4HB) domain and dissociating its auto-inhibitory region (Dovey CM et al. 2018; McNamara DE et al. 2019). This is consistent with the findings that inositol polyphosphate kinases (IPK) IPMK and ITPK1 are essential regulators of MLKL-mediated necroptosis in a forward genetic screen performed with the human haploid cell line HAP1 (Dovey CM et al. 2018). Subsequent genetic deletion of IPK genes IPMK, ITPK1 and IPPK of the IP code metabolic pathway blocked MLKL-mediated necroptosis in human colon adenocarcinoma HT-29 cells (Dovey CM et al. 2018; McNamara DE et al. 2019). Activating IPs bind three sites on MLKL with affinity of 100-600 μM to destabilize contacts between the auto-inhibitory region and NED of MLKL. This liberates NED, promoting oligomerization and activation of MLKL (McNamara DE et al. 2019).
Identifier: R-HSA-5357927
Species: Homo sapiens
Compartment: cytosol
Mixed lineage kinase domain-like protein (MLKL) was found to form oligomers that translocate to and mediate permeabilisation of plasma membrane (Hildebrand JM et al. 2014; Davies KA et al. 2018; Petrie EJ et al. 2018; Samson AL et al. 2020). The oligomerization of MLKL was observed in a variaty of human (colon adenocarcinoma HT-29, FADD-null Jurkat cells, leukemic monocyte lymphoma U937) and mouse cells upon necroptosis induced by (TNF+Smac mimetic+caspase inhibitor z-VAD-FMK) (Cai Z et al. 2014; Chen X et al. 2014; Davies KA et al. 2018; Petrie EJ et al. 2018). The precise oligomeric form of MLKL that mediates plasma membrane disruption has been highly debated (Chen X et al. 2014; Cai Z et al. 2014; Davies KA et al. 2018; Petrie EJ et al. 2018; reviewed by Petrie EJ 2017). Native mass spectrometry (MS) defined the human MLKL oligomer as a tetramer (Petrie EJ et al. 2018). Low-resolution techniques including cross-linking and deuterium exchange MS and small angle X-ray scattering (SAXS) showed that MLKL exists in equilibrium between a monomer and a daisy chain tetramer with the N-terminal four‑helix bundle (4HB) of one monomer binding to the pseudokinase domain (psKD) of another monomer (Petrie EJ et al. 2018). Cys-oxidation under nonreducing conditions and crosslinking analyses detected tetramers and octamers in L929 murine fibroblast and HEK293 cells undergoing TNF-mediated necroptosis, although the relationship of these disulfide crosslinks to MLKL’s killer function remains unknown (Huang D et al. 2017). While trimers, tetramers, hexamers were reported in studies with the recombinant MLKL protein (Cai Z et al. 2014; Chen X et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014; Petrie EJ et al. 2018), single-cell imaging approaches revealed that endogenous human phosphorylated MLKL assembles on necrosomes into higher order species that are heterogeneous in MLKL stoichiometry (Samson AL et al. 2020). RIPK3-mediated phosphorylation of MLKL’s pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of 4HB ‘executioner’ domain leads to cell death (Hildebrand JM et al 2014; Petrie EJ et al. 2018). Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer (Petrie EJ et al. 2018). Despite lacking catalytic activity, the pseudokinase domain of MLKL has retained the ability to bind ATP (Murphy JM et al. 2013, 2014; Petrie EJ et al. 2018). The ATP binding has been shown to negatively regulate MLKL-mediated membrane permeabilization by destabilizing the MLKL tetramers and shifting the tetramer:monomer equilibrium toward the monomeric state (Petrie EJ et al. 2018). The two interdomain helices, termed the ‘brace’ helices, contribute to MLKL oligomerization by connecting phosphorylation of the pseudokinase domain to the release or activation of the 4HB domain executioner function to enable its participation in membrane localisation, permeabilization and cell death (Davies KA et al. 2018). In addition, the autoinhibited N-terminal 4HB of human MLKL is activated by inositol phosphate metabolites IP4, IP5 and IP6 produced by inositol phosphate multikinase (IPMK), inositol tetrakisphosphate kinase 1 (ITPK1) and inositol pentakisphosphate 2-kinase (IPPK) (Dovey CM et al. 2018; McNamara DE et al. 2019). These inositol phosphates promote MLKL-mediated necroptosis through directly binding 4HB domain of MLKL and dissociating its auto-inhibitory region (McNamara DE et al. 2019). Oligomers of MLKL translocate to membrane compartments (Cai Z et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014; Hildebrand JM et al. 2014; Davies KA et al. 2018; Petrie EJ et al. 2020; Samson AL et al. 2020). MLKL oligomerization and membrane translocation are hallmarks of the necroptosis pathway, which plays a crucial role in the host defense response against many pathogens (Upton JW et al. 2017). In response, pathogens have developed different strategies to target the host necroptosis machinery (Upton JW et al. 2017; Pearson JC et al. 2017; Petrie EJ et al. 2019; Gaba A et al. 2019).

Even though the stoichiometry of the MLKL oligomerization in the Reactome event depicts MLKL homotetramer, the endogenous MLKL was shown to assemble on necrosomes into higher order species that are heterogeneous in MLKL stoichiometry (Samson AL et al. 2020).

Pathway (2 results from a total of 2)

Identifier: R-HSA-1855191
Species: Homo sapiens
Within the nucleus, inositol polyphosphate multikinase (IPMK), inositol-pentakisphosphate 2-kinase (IPPK), inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) produce IP5, IP6, IP7, and IP8 inositol phosphate molecules (Irvine & Schell 2001, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010, Nalaskowski et al. 2002, Chang et al. 2002, Chang & Majerus 2006, Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008, Mulugu et al. 2007).
Identifier: R-HSA-1483249
Species: Homo sapiens
Inositol phosphates (IPs) are molecules involves in signalling processes in eukaryotes. myo-Inositol consists of a six-carbon cyclic alcohol with an axial 2-hydroxy and five equatorial hydroxyls. Mono-, di-, and triphosphorylation of the inositol ring generates a wide variety of stereochemically distinct signalling entities. Inositol 1,4,5-trisphosphate (I(1,4,5)P3), is formed when the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is hydrolysed by a phospholipase C isozyme. An array of inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are synthesised by the action of various kinases and phosphatases in the cytosol. These species then transport between the cytosol and the nucleus where they are acted on by inositol polyphosphate multikinase (IPMK), inositol-pentakisphosphate 2-kinase (IPPK), inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2), to produce IP5, IP6, IP7, and IP8 molecules. Some of these nuclear produced IPs transport back to the cytosol where they are converted to an even wider variety of IPs, by kinases and phosphatases, including the di- and triphospho inositol phosphates aka pyrophosphates (Irvine & Schell 2001, Bunney & Katan 2010, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010).
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