Mammalian Phosphatidylinositol 4-Kinases

Abstract

Three phosphatidylinositol 4-kinase isoforms, PI4K 230, 92 and 55 have been cloned and sequenced allowing a much wider characterization than the previously employed enzymological typing into type II and III enzymes. PI4K 230 and 92 contain a highly conserved catalytic core, PI4K55 one with a much lower degree of similarity. Candidate kinase motifs, deduced from the protein kinase super family, are absolutely conserved in all isoforms. Kinase activities are described based on their sensitivity and reactivity towards wortmannin, phenylarsine oxide (PAO) and 5'-p-fluorosulfonylbenzoyladenosine (FSBA). Localization of all isoforms in the cell is reported. All enzymes contain nuclear localization and export sequence motifs (NLS and NES) leading to the expectation that they can be transferred to the nucleus. PI4K230 has been found in the nucleolus, PI4K92 in the nucleus, additionally further broadening the function of these enzymes. In the cytoplasm of neuronal cells, PI4K230 is distributed evenly on membranes that are ultra structurally cisterns of the rough endoplasmatic reticulum, outer membranes of mitochondria, multivesicular bodies, and are in close vicinity of synaptic contacts. PI4K92 is functionally characterized as a key enzyme regulating Golgi disintegration/reorganization during mitosis probably via phosphorylation by cyclin-dependent kinases on well-defined sites. PI4K55 is involved in the production of second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (InsP3) at the plasma membrane, moreover, in the endocytotic pathway in the cytoplasm.

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

“…Phosphatidylinositol 4-kinases (PI4Ks) are best known for providing the substrate for phosphatidylinositol 3-kinase (PI3K) and for producing second messengers (Gehrmann and Heilmeyer, 1998;Heilmeyer et al, 2003;Di and De, 2006). Two kinds of PI4Ks have been characterized, namely type III phosphatidylinositol (PI) 4-kinases (PI4KIIIa and PI4KIIIb) and type II PI 4-kinases (PI4KIIa and PI4KIIb) (Heilmeyer et al, 2003).…”

“…Two kinds of PI4Ks have been characterized, namely type III phosphatidylinositol (PI) 4-kinases (PI4KIIIa and PI4KIIIb) and type II PI 4-kinases (PI4KIIa and PI4KIIb) (Heilmeyer et al, 2003). Recent evidence suggests that PI(4)P produced by PI4KIIa has an independent function in its own right beyond that of generally providing a substrate for PI3K.…”

Nucleolar localization of phosphatidylinositol 4‐kinase PI4K230 in various mammalian cells

“…Several observations indicate the presence of phosphoinositides and lipid signaling in the nucleus, too (5–13). Nuclear localization of phosphoinositide kinases, such as phosphatidylinositol 3‐kinase (PI3K) (14, 15), phosphatidylinositol 4‐phosphate 5‐kinase (11, 16), phosphatidylinositol 5‐phosphate 4‐kinase (16, 17), and phosphatidylinositol 4‐kinases (PI4Ks) (13, 18–21), in mammalian cells suggest their involvement in the regulation of cell cycle and structural organization/reorganization of the chromatin during mitosis (for review see Ref 22…”

Hepatitis C Virus Subverts Human Choline Kinase-α To Bridge Phosphatidylinositol-4-Kinase IIIα (PI4KIIIα) and NS5A and Upregulates PI4KIIIα Activation, Thereby Promoting the Translocation of the Ternary Complex to the Endoplasmic Reticulum for Viral Replication

“…Given the multiple intracellular localization sites of NS5A in perinuclear membranes, such as those of the ER, Golgi complex, and lipid droplets (5, 43), as well as the localization sites of PI4KIIIα in the ER (9, 10), Golgi complex-associated membrane vesicles (13), and the nucleolus (14), it would be difficult to determine unambiguously where PI4KIIIα and NS5A localize when PI4P synthesis is interrupted by CK37 or AL-9. Here we used an ER-residing marker, CALR, to investigate the transport or “translocation” of PI4KIIIα, NS5A, and hCKα to the PI4P-enriched, ER-associated membrane, because HCV replication increases their localization to the CALR-associated membrane.…”

“…PI4KIIIα also regulates the PI4P level at the plasma membrane (11, 12). PI4KIIIα can also be found in close association with the membranes of the Golgi vesicles and vacuoles (13) and in the nucleolus (14). PI4KIIIβ is the lipid kinase primarily responsible for the PI4P pool in the Golgi apparatus (15, 16), and it also localizes on the lysosome to maintain lysosomal membrane integrity (17).…”