Inositol pyrophosphates as mammalian cell signals

Abstract

Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphosphate (IP₆) to generate the pyrophosphate IP₇. Initial insights into functions of these substances derived primarily from yeast, which contain a single isoform of IP₆ kinase (yIP₆K), as well as from the slime mold Dictyostelium. Mammalian functions for inositol pyrophosphates have been investigated by using cell lines to establish roles in various processes, including insulin secretion and apoptosis. More recently, mice with targeted deletion of IP₆K isoforms as well as the related inositol polyphosphate multikinase (IPMK) have substantially enhanced our understanding of inositol polyphosphate physiology. Phenotypic alterations in mice lacking inositol hexakisphosphate kinase 1 (IP₆K1) reveal signaling roles for these molecules in insulin homeostasis, obesity, and immunological functions. Inositol pyrophosphates regulate these processes at least in part by inhibiting activation of the serine-threonine kinase Akt. Similar studies of IP₆K2 establish this enzyme as a cell death inducer acting by stimulating the proapoptotic protein p53. IPMK is responsible for generating the inositol phosphate IP₅ but also has phosphatidylinositol 3-kinase activity--that participates in activation of Akt. Here, we discuss recent advances in understanding the physiological functions of the inositol pyrophosphates based in substantial part on studies in mice with deletion of IP₆K isoforms. These findings highlight the interplay of IPMK and IP₆K in regulating growth factor and nutrient-mediated cell signaling.

Fig. 1

Inositol polyphosphate biosynthetic pathway. IP₃K or IPMK phosphorylates IP₃ to generate IP₄ [Ins(1,3,4,5)P₄ or Ins(1,4,5,6)P₄]. Further sequential phosphorylation of IP₄ by IPMK and IP₅K yields IP₆ (, , , –36, 44). IP₆Ks pyrophosphorylate the 5 position, generating 5-PP-IP₄ from IP₅, 5-PP-IP₅ (5-IP₇) from IP₆, and 1-/3-,5-(PP)2-IP₄ (1,5-IP₈) from 1-/3-PP-IP₅ (7, 17, 19, 20). 5-IP₇ is the predominant inositol pyrophosphate in mammals. PP-IP₅Ks, the human Vip1 isoforms, pyrophosphorylate the 1 or 3 position to yield 1-/3-PP-IP₅ (depicted as 1-IP₇ for simplicity) from IP₆, or 1-/3-,5-(PP)2-IP₄ (1,5-IP₈) from 5-IP₇, and physiologically, they are primarily involved in generating IP₈. DIPPs dephosphorylate inositol pyrophosphates to IP₆ or IP₅ (32, 47).

Fig. 2

Inositol polyphosphates in insulin homeostasis. Inositol pyrophosphates (5-IP₇) facilitate insulin secretion from pancreatic β cells (50). The secreted hormone signals through its receptors in insulin-responsive tissues and activates the protein kinase Akt through the PI 3-kinase pathway. Insulin also increases inositol pyrophosphate concentrations, which decreases Akt activity in liver, skeletal muscles, and adipose tissues (11) and thereby maintains homeostasis between insulin release and its signaling.

Fig. 3

Inositol poly- and pyrophosphates in mammalian cellular signaling networks. The combined soluble inositol phosphate kinase activities of IP₃K, IPMK, and IP₅K generate IP₅ and IP₆ from IP₃, which are precursors of inositol pyrophosphates. 5-IP₇ inhibits Akt activity, which decreases mTORC1-mediated protein translation and increases GSK3β-mediated glycogenolysis, adipogene-sis (11), and behavior. IP₅ also inhibits Akt signaling (124, 125). Inhibition by 5-IP₇ of Akt diminishes neutrophil phagocytic functions (12). 5-IP₇ regulates the release of virus like particles through its pyrophosphorylating activities (85). IPMK acts as a PI 3-kinase to activate Akt (25, 26). In a manner independent of its catalytic activity, IPMK binds, stabilizes, and activates the mTORC1 complex (27). Thus, IPMK enhances or inhibits Akt signaling, respectively, by means of its PI 3-kinase and soluble inositol phosphate kinase activities. IP₆K2 is a proapoptotic protein regulated by HSP90, which binds and inactivates it (58), as well as by CK2, which phosphorylates IP₆K2 to enhance its proteasomal degradation (59). Apoptotic stimuli stabilize, activate, and facilitate nuclear translocation of IP₆K2, where it binds p53 and augments p53’s apoptotic actions (13).