The inositol pyrophosphates IP7 and IP8 contain highly energetic pyrophosphate bonds. Although implicated in various biologic functions, their molecular sites of action have not been clarified. Using radiolabeled IP7, we detected phosphorylation of multiple eukaryotic proteins. We also observed phosphorylation of endogenous proteins by endogenous IP7 in yeast. Phosphorylation by IP7 is nonenzymatic and may represent a novel intracellular signaling mechanism.
The authors note that Figs. 1b, 1d, 1g, and 4a have been revised to include dividing lines between lanes to show where nonessential lanes were removed from a single original gel. Figs. 2c, 2d, and 3c have been revised to include boxes to indicate samples run on different gels, under the same conditions; these gels are aligned with respect to the indicated molecular weight markers. Figs. 4b and 4c have been revised to eliminate errors that occurred in the original version during file conversion. The changes were made to comply with the PNAS policy that requires dividing lines whenever entire nonessential lanes have been removed from a single original gel, and clear demarcation of samples run on separate gels. These changes do not affect the data presented nor the conclusions of the article. The corrected figures and their legends appear below.
Inositol pyrophosphates, also designated inositol diphosphates, possess high-energy -phosphates that can pyrophosphorylate proteins and regulate various cellular processes. They are formed by a family of inositol hexakisphosphate kinases (IP6Ks). We have created mice with a targeted deletion of IP6K1 in which production of inositol pyrophosphates is markedly diminished. Defects in the mutants indicate important roles for IP6K1 and inositol pyrophosphates in several physiological functions. Male mutant mice are sterile with defects in spermiogenesis. Mutant mice are smaller than wild-type despite normal food intake. The mutants display markedly lower circulating insulin.inositol phosphate kinase ͉ inositol polyphosphate ͉ knockout mouse N umerous inositol phosphates regulate biological functions with the best characterized, inositol-1,4,5-trisphosphate (IP 3 ), releasing intracellular calcium (1). Recent attention has focused on the inositol pyrophosphates, also designated inositol diphosphates, of which the best studied are diphosphoinositol pentakisphosphate [5-PP-I(1,2,3,4,6)P 5 , here designated IP 7 ] and bisdiphosphoinositol tetrakisphosphate ([PP] 2 -IP 4 , IP 8 ) (2-4). These compounds are synthesized by a family of three inositol hexakisphosphate (IP 6 ) kinases (IP6Ks) (5-7). Inositol pyrophosphates have been implicated in a variety of physiologic functions including apoptosis (8, 9), endocytosis (10, 11), telomere length maintenance (12, 13), and chemotaxis (14). Additionally, another form of IP 7 , tentatively identified as 4/6-PP-IP 5 , is formed by the Vip1 enzyme in yeast and is implicated in the regulation of cell morphology, cell growth, and phosphate homeostasis (15, 16). Shears et al. have established that the mammalian Vip1 ortholog physiologically synthesizes IP 8 , which is involved in osmotic regulation (17,18). Inositol pyrophosphates may exert their functions in two ways, by binding to proteins or via phosphorylation. IP 7 can directly bind cytosolic proteins, such as the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor (CKI) complex, required for phosphate homeostasis in yeast (19). IP 7 can also compete with membrane phosphoinositides for binding to phosphoinositide-binding modules such as PH domains, as observed during chemotactic regulation in Dictyostelium (14). In addition, IP 7 physiologically phosphorylates proteins in a nonenzymatic fashion, analogous to S-nitrosylation, whereby the -phosphate is transferred from IP 7 to previously phosphorylated proteins; hence, IP 7 pyrophosphorylates proteins (20, 21).The various mammalian IP6Ks serve diverse functions. IP6K2 regulates apoptotic cell death (8,9,22,23). IP6K1 has been implicated in the disposition of insulin and glucose. A putative disruption of the IP6K1 gene has been described in a family with type 2 diabetes (24). Illies et al. recently showed that selective depletion of IP6K1 by RNA interference in pancreatic beta cells impairs insulin secretion (25). To elucidate the physiologic role of IP6K1, we created mice with a ta...
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