PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 17233588

Type II PtdInsP kinases: location, regulation and function.

Jonathan H Clarke·Jonathan P Richardson·Katherine A Hinchliffe·Robin F Irvine
View original source ↗Export metadata ↓

Abstract

The regulation of the synthesis of PtdIns(4,5)P2 is emerging as being as complex as we might expect from the multi-functional nature of this lipid. In the present chapter we focus on one aspect of inositide metabolism, which is the functions of the Type II PIPkins (Type II PtdInsP kinases). These are primarily PtdIns5P 4-kinases, although in vitro they will also phosphorylate PtdIns3P to PtdIns(3,4)P2. Thus they have three, not necessarily exclusive, functions: to make PtdIns(4,5)P2 by a quantitatively minor route, to remove PtdIns5P and to make PtdIns(3,4)P2 by a route that does not involve a Class I PtdIns 3-kinase. None of these three possible functions has yet been unambiguously proven or ruled out. Of the three isoforms, alpha and beta are widely expressed, the IIalpha being predominantly cytosolic and the IIbeta primarily nuclear. PIPkin IIgamma has a much more restricted tissue expression pattern, and appears to be localized primarily to intracellular vesicles. Here we introduce in turn each of the three Type II PIPkins, and discuss what we know about their localization, their regulation and their function.

Explore related subjects

Amino Acid SubstitutionAnimalsHumansIsoenzymesMetabolic Networks and PathwaysMinor Histocompatibility AntigensPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositol PhosphatesPhosphatidylinositolsPhosphotransferasesPhosphotransferases (Alcohol Group Acceptor)Journal ArticleResearch Support, Non-U.S. Gov'tReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Jonathan H Clarke, Jonathan P Richardson, Katherine A Hinchliffe, Robin F Irvine. 2007. Type II PtdInsP kinases: location, regulation and function.. https://doi.org/10.1042/bss0740149

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway.

Mitotic Aurora-A is an oncogene, which undergoes a cell-cycle-dependent regulation of both its synthesis and degradation. Overexpression of Aurora-A leads to aneuploidy and cellular transformation in cultured cells. It has been shown that the cell-cycle-dependent turnover of Aurora-A is mediated by Cdh1 (CDC20 homologue 1) through the anaphase-promoting complex/cyclosome (APC/C)-ubiquitin-proteasome pathway. We have described previously the identification of an Aurora-A kinase interacting protein, AURKAIP1 (formerly described as AIP), which is also involved in the destabilization of Aurora-A through the proteasome-dependent degradation pathway. In an attempt to investigate the mechanism of AURKAIP1-mediated Aurora-A degradation, we report here that AURKAIP1 targets Aurora-A for degradation in a proteasome-dependent but Ub (ubiquitin)-independent manner. AURKAIP1 inhibits polyubiquitination of Aurora-A. A non-interactive AURKAIP1 mutant that cannot destabilize Aurora-A restores ubiquitination of Aurora-A. An A-box mutant of Aurora-A, which cannot be targeted for proteasome-dependent degradation by Cdh1, can still be degraded by AURKAIP1. Inhibition of cellular ubiquitination either by expression of dominant negative Ub mutants or by studies in ts-20 (temperature sensitive-20) CHO (Chinese-hamster ovary) cell line lacking the E1 Ub activating enzyme at the restrictive temperature, cannot abolish AURKAIP1-mediated degradation of Aurora-A. AURKAIP1 specifically decreases the stability of Aurora-A in ts-20 CHO cells at the restrictive temperature, while cyclinB1 and p21 are not affected. This demonstrates that there exists an Ub-independent alternative pathway for Aurora-A degradation and AURKAIP1 promotes Aurora-A degradation through this Ub-independent yet proteasome-dependent pathway.

Amino Acid Substitution↗
PubMed2007

The role of the synergistic phosphate anion in iron transport by the periplasmic iron-binding protein from Haemophilus influenzae.

The acquisition of iron from transferrin by Gram-negative bacterial pathogens is dependent on a periplasmic ferric-ion-binding protein, FbpA. FbpA shuttles iron from the outer membrane to an inner membrane transport complex. A bound phosphate anion completes the iron co-ordination shell of FbpA and kinetic studies demonstrate that the anion plays a critical role in iron binding and release in vitro. The present study was initiated to directly address the hypothesis that the synergistic anion is required for transport of iron in intact cells. A series of site-directed mutants in the anion-binding amino acids of the Haemophilus influenzae FbpA (Gln-58, Asn-175 and Asn-193) were prepared to provide proteins defective in binding of the phosphate anion. Crystal structures of various mutants have revealed that alteration of the C-terminal domain ligands (Asn-175 or Asn-193) but not the N-terminal domain ligand (Gln-58) abrogated binding of the phosphate anion. The mutant proteins were introduced into H. influenzae to evaluate their ability to mediate iron transport. All of the single site-directed mutants (Q58L, N175L and N193L) were capable of mediating iron acquisition from transferrin and from limiting concentrations of ferric citrate. The results suggest that the transport of iron by FbpA is not dependent on binding of phosphate in the synergistic anion-binding site.

Amino Acid Substitution↗
PubMed2007

Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells.

Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-kappaB regulation and caspase-1-mediated maturation of interleukin 10. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.

Amino Acid Substitution↗