title: Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels.
abstract: Polyphosphate (polyP), a polymer of orthophosphate moieties released from the dense granules of activated platelets, is a procoagulant agent. Inositol pyrophosphates, another group of phosphate-rich molecules, consist of mono- and diphosphates substituted on an inositol ring. Diphosphoinositol pentakisphosphate (IP7), the most abundant inositol pyrophosphate, is synthesized on phosphorylation of inositol hexakisphosphate (IP6) by IP6 kinases, of which there are 3 mammalian isoforms (IP6K1/2/3) and a single yeast isoform. Yeast lacking IP6 kinase are devoid of polyP, suggesting a role for IP6 kinase in maintaining polyP levels. We theorized that the molecular link between IP6 kinase and polyP is conserved in mammals and investigated whether polyP-dependent platelet function is altered in IP6K1 knockout (Ip6k1(-/-)) mice. We observe a significant reduction in platelet polyP levels in Ip6k1(-/-) mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots was reduced in Ip6k1(-/-) mice, thereby altering clot ultrastructure, which was rescued on the addition of exogenous polyP. In vivo assays revealed longer tail bleeding time and resistance to thromboembolism in Ip6k1(-/-) mice. Taken together, our data suggest a novel role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels.
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors.forename: Somadri
authors.initials: S
authors.lastname: Ghosh
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Shukla
authors.forename: Komjeti
authors.initials: K
authors.lastname: Suman
authors.forename: B Jyothi
authors.initials: BJ
authors.lastname: Lakshmi
authors.forename: R
authors.initials: R
authors.lastname: Manorama
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.forename: Rashna
authors.initials: R
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D006487:Hemostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000502:physiology*; D010833:Phytic Acid / Q000378:metabolism; D011122:Polyphosphates / Q000378:metabolism*; D011655:Pulmonary Embolism / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013923:Thromboembolism / Q000097:blood
chemical_list: D019007:P-Selectin; D011122:Polyphosphates; D010833:Phytic Acid; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase; D013917:Thrombin