Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Abstract

Inositol phosphate kinase 2 (Ipk2), also known as IP multikinase IPMK, is an evolutionarily conserved protein that initiates production of inositol phosphate intracellular messengers (IPs), which are critical for regulating nuclear and cytoplasmic processes. Here we report that Ipk2 kinase activity is required for the development of the adult fruit fly epidermis. Ipk2 mutants show impaired development of their imaginal discs, the primordial tissues that form the adult epidermis. Although disk tissue seems to specify normally during early embryogenesis, loss of Ipk2 activity results in increased apoptosis and impairment of proliferation during larval and pupal development. The proliferation defect is in part attributed to a reduction in JAK/ STAT signaling, possibly by controlling production or secretion of the pathway's activating ligand, Unpaired. Constitutive activation of the JAK/STAT pathway downstream of Unpaired partially rescues the disk growth defects in Ipk2 mutants. Thus, IP production is essential for proliferation of the imaginal discs, in part, by regulating JAK/STAT signaling. Our work demonstrates an essential role for Ipk2 in producing inositide messengers required for imaginal disk tissue maturation and subsequent formation of adult body structures and provides molecular insights to signaling pathways involved in tissue growth and stability during development.inositol phosphates | inositol phosphate multikinase | Ipk2 | IPMK | Upd A t the confluence of numerous signaling pathways is phospholipase C (PLC)-mediated production of the second messenger inositol 1,4,5-trisphosphate (IP 3 ), a key regulator of intracellular calcium release (1). IP 3 also serves as an essential substrate for the synthesis of inositol phosphates (IPs) and pyrophosphates (PP-IPs) that are critical for eukaryotic cellular function in their own right (2-6). Phosphorylation of IP 3 by conserved inositol phosphate kinases (IPKs) leads to the synthesis of complex pools of different IP species (6). Insights into the cellular functions of IPs have been gleaned by perturbing their synthesis through genetic manipulations of the IPKs. Consequently, defects in specific cellular processes were attributed to losses of particular IPs. This revealed that IPs are specific regulators of diverse cellular processes, such as transcription, chromatin remodeling, DNA repair, RNA editing, and RNA export (3-7).An essential enzyme for the conversion of IP 3 to the array of IP and PP-IP species found in cells is the evolutionarily conserved inositol phosphate kinase 2 (Ipk2, Fig. 1A), which is also known as IP multikinase (IPMK) (4). Ipk2 was first identified in yeast as a nuclear enriched protein whose activities toward the 6-and 3-positions on the inositol ring sequentially convert IP 3 to IP 4 , and then IP 5 (Fig. 1A) (8-10). Yeast Ipk2 mutants that fail to produce IP 4 and IP 5 exhibit defects in transcriptional responses and chromatin remodeling (3). Additional "multikinase" activities described for certain Ipk2 orthologs indicate an array ...

Inositol polyphosphate multikinase regulation ofTrypanosoma bruceilife stage development

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