The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

Abstract

The inositol polyphosphates are a group of multifunctional signaling metabolites whose synthesis is catalyzed by a family of inositol kinases that are evolutionarily conserved from yeast to humans. Inositol polyphosphate multikinase (IPMK) was first identified as a subunit of the arginine-responsive transcription complex in budding yeast. In addition to its role in the production of inositol tetrakis- and pentakisphosphates (IP₄ and IP₅), IPMK also exhibits phosphatidylinositol 3-kinase (PI3-kinase) activity. Through its PI3-kinase activity, IPMK activates Akt/PKB and its downstream signaling pathways. IPMK also regulates several protein targets non-catalytically via protein-protein interactions. These non-catalytic targets include cytosolic signaling factors and transcription factors in the nucleus. In this review, we highlight the many known functions of mammalian IPMK in controlling cellular signaling networks and discuss future challenges related to clarifying the unknown roles IPMK plays in physiology and disease.

Keywords: IPMK; PI3-kinase; inositol; inositol phosphates; inositol polyphosphate multikinase.

Fig. 1

The functions of IPMK in inositol biosynthesis pathway. IPMK possesses the activity of phosphorylating IP₃ to IP₄ as well as IP₄ to IP₅. IPMK also acts as a phosphoinositide kinase, which produces PIP₃ from PIP₂.

Fig. 2

Versatile signaling actions of mammalian IPMK. As a PI3-kinase, IPMK activates Akt signaling. Water-soluble, inositol phosphates produced from IPMK such as Ins(1,4,5,6)P₄ appears essential for class I HDAC function. Independent of its catalytic activity, IPMK directly binds to various cytosolic signaling factors, thereby regulating multiple signaling networks. Inside the nucleus, IPMK is a key node of molecular events (e.g., selective mRNA export, transcription). It acts as a transcription coactivator via forming complexes with transcription factors as well as epigenetic regulators. See main text for further details. Blue lines indicate catalytic activity-dependent IPMK actions. Red lines designate IPMK-binding partners which are non-catalytically regulated by IPMK.