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Home , Inositol phosphate, Kinase

SnapShot: Ace J. Hatch and John D. York HHMI, Pharmacology and Biology, , Duke University, Durham, NC 27710, USA

PLC-dependent IP code

GPCR RTK O

O O O O O

5-PP-IP4 IP4 5-IP7 O O O O O O PIP2 O IP6K O IP6K O VIP1 O O O 2 O ITPK1 O 13 O PLC 2 O O O O O O O O 4 6 13 O 5 IP3 IPMK IP4 IPMK IP5 IPK1 IP6 1,5-IP8 4 6 O O 5 O O O O O O O O O O O O O O YEAST MAMMALIAN IP3K VIP1 IP6K IPMK PLC1 PLCβ, γ, δ, ε, ζ, η O - IP3KA, B, C - ITPK1 (IP56K) O O O O O O O O IPK2(ARG82) IPMK (IPK2) IP4 IP3 IP4 1-IP7 IPK1 IPK1 (IP5K) INPP5 ITPK1 KCS1 IP6K1, 2, 3 O O O O O O VIP1 VIP1, 2 (PPIP5K1, 2) O O

Ion channels sensing Cl- Abundant phosphate MCM1 ARG80 CIC3 P PLASMA MEMBRANE - Pho80 Cl channel Pho4 Kinase Kinase Assembly Pho85 independent CYTOPLASM activity 2 O PIP2 Pho81 13 CYTOPLASM NUCLEUS IPK2 ARG81 4 6 Phosphate starvation MCM1-ArgR O 5 O complex O O IP4 O O O O O

O O 1-IP7 Kinase Activation dependent IP3 O O Transcription O O O activated Pho80 IP4 O X Pho4 O O Pho85 Kinase activity IP receptor blocked O 3 ENDOPLASMIC Pho81 RETICULUM Ca2+ CYTOPLASM NUCLEUS NUCLEUS mRNA export and Insulin and AKT Embryonic development Translation termination Effects of IP kinase deficiency O IPMK (IPK2): Multiple defects, death by embryonic day 10 (mice) O O Insulin IPK1: Cillia are shortened and immotile IP6 AKT resistance causing patterning defects (zebra sh) O O Multiple defects, death by Ribosome O embryonic day 8.5 (mice) GleI eRF1 Insulin GSK3β Dbp5 ITPK1 (IP56K): Neural tube defects (mice) STOP AAAAA O IP3K: Sterility (nematodes) mRNA O O eRF3 5-IP Multiple defects in immune CYTOPLASM 7 and neural cell development (mammals) O O Adipogenesis Nuclear mRNA export O IP6K2: Misregulated hedgehog signaling O results in patterning defects (zebra sh) O O O IP6 CYTOPLASM O O Other roles GleI O CYTOPLASM Dbp5 O O O Inositol diphosphates can transfer phosphate nonenzymatically to phosphoserine to 2+ IP6 Ca , final release generate diphosphate modi ed NUCLEUS Nuclear pore O O complex IP6K1 (KCS1) generated inositol diphosphates mRNA O are required for proper regulation of telomere RRP vesicles length IP structural cofactors O Ipk2 regulates activity of Swi/Snf and Ino80 Insulin chromatin-remodeling complexes in yeast O O IP6K1 (KCS1) is required for proper vacuole 5-IP7 morphology and responses to osmotic stress O O Secretory IP stimulates nonhomologous end joining O vesicles 6 through interactions with Ku O

IP6 (phytate) is important in plant biology and agriculture as a major phosphate store ADAR2 TIR1 β CELL

1030 Cell 143, December 10, 2010 ©2010 Elsevier Inc. DOI 10.1016/j.cell.2010.11.045 See online version for legend and references. SnapShot: Inositol Phosphates Ace J. Hatch and John D. York HHMI, Pharmacology and Cancer Biology, Biochemistry, Duke University, Durham, NC 27710, USA

PLC-Dependent IP Code Inositol phosphates (IPs) are signaling molecules found in all . Inositol is a six-carbon cyclic with an axial 2-hydroxyl (depicted with heavy tapered lines) and

five equatorial hydroxyls. Mono- and diphosphorylation of the inositol scaffold generate a wide array of stereochemically distinct signaling molecules. Soluble IP3 is formed by hydrolysis of the inositol PIP2 via (PLC) isozymes. PLC is stimulated by a host of extracellular signals acting through G -coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). An array of lipid-derived IP species arise through the actions of four evolutionarily conserved kinases (the common names are shown in the

figure and table, and aliases are shown in parentheses). multi-kinase, IPMK (IPK2 or ARG82), produces I(1,3,4,5,6)P5 from IP3 by sequential

of the 6- and 3-positions. It also possesses 5-kinase activity toward I(1,3,4,6)P4 (in total eight substrates have been proposed including the lipid PIP2—hence the name “multi-

kinase”). IPK1 (IP5K) generates IP6 from IP5 by phosphorylation at the 2-position. IP6K (KCS1, IHPK) phosphorylates the 5-position of IP5, IP6, and IP7 to generate diphospho- inositol phosphates (PP-IPs) 5-PP-IP4, 5-IP7, and 1,5-IP8, respectively. VIP isoforms (PPIP5K, IP7K) generate diphospho-inositol products through a distinct 1-kinase, or possibly

its enantiomeric 3-kinase, activity yielding 1-IP7 and 1,5-IP8. In multicellular organisms there are up to two additional IP kinases (see table in figure). Plants and mammals have

an ITPK (5/6-kinase, IP56K) that phosphorylates I(1,3,4)P3 at either the 5- or 6-position to generate I(1,3,4,5)P4 or I(1,3,4,6)P4, respectively. ITPK1 is also a reversible

1-kinase/ that controls the levels of I(3,4,5,6)P4. Flies and mammals have IP3 3-kinases (IP3K) that selectively phosphorylate I(1,4,5)P3 to I(1,3,4,5)P4. Additionally, several that add to the diversity of IP species have been omitted for clarity; however we do show INPP5, a 5-phosphatase for which ten exist in mammals, in the context of its role in generating the I(1,3,4)P3 utilized by ITPK. In total, close to forty of the theoretical 728 inositol mono- and diphosphorylated species have been identified in eukaryotic cells representing the building blocks of what we depict as a PLC-dependent IP code.

Functional Roles of IPs Ion Channels

Soluble IP3 generated by the hydrolysis of PIP2 through receptor-activated PLC isoforms (either PLCβ or PLCγ) directly binds endoplasmic reticulum-resident calcium channels

and regulates their permeability. The flux of intracellular calcium has many biological effects, and the role of IP3 in regulating calcium channels has been studied in great detail

thereby serving as a canonical second messenger paradigm. Additionally, I(3,4,5,6)P4 generated by the 1-phosphatase activity of ITPK1 regulates the permeability of the plasma membrane resident ClC3 chloride channel. Phosphate Sensing The Pho80-Pho85-Pho81 -CDK-CDKi complex acts to phosphorylate the Pho4 , a modification that maintains its cytoplasmic localization when envi-

ronmental phosphate is abundant. When environmental phosphate is scarce, Vip1-produced 1-IP7 binds to the Pho80-Pho85-Pho81 complex inhibiting its kinase activity. Unphosphorylated Pho4 is then able to accumulate in the nucleus and initiate the transcription of genes required for phosphate scavenging. Transcription In yeast, Ipk2 is one of four components of the Mcm1-ArgR transcription complex responsible for regulating the transcriptional response to environmental arginine. Although Ipk2 does not bind DNA directly, it assembles with the complex in response to nutrient deprivation, providing both kinase-independent and -dependent functionalities that mediate changes in transcription. Insulin Secretion and AKT IPs are implicated in several different aspects of insulin secretion from pancreatic β cells. The regulation of intracellular Ca2+ is important for the control of secretory vesicle fusion 2+ 2+ and insulin release. IP3 regulates Ca release from intracellular stores and IP6 regulates the flux through L-type Ca channels. 5-IP7 generated by IP6K1 in β cells has been shown to stimulate insulin secretion from the readily releasable pool (RRP) of vesicles. A paper published in this issue of Cell reports a role for IP6K-generated 5-IP7 in regulating AKT signaling in response to insulin stimulation. Deleting IP6K in mice results in insulin hypersensitivity and increased fatty acid and protects against age-dependent insulin resistance analogous to human type 2 diabetes. Embryonic Development Mutations in individual kinases within the IP pathway cause multiple developmental defects. In mice loss of IPMK (Ipk2) or IPK1 is embryonic lethal. Zebrafish show randomization of left-right asymmetry when IPK1 is depleted. This defect is caused by shortened cilia that cannot beat properly. ITPK loss in mice results in profound neural tube defects. IP6K mutant organisms show sterility and signaling pathway defects. IP3K-deficient organisms show sterility and immunological and neural defects. The broad spectrum of defects across species has necessitated the use of multiple model systems in the study of the IP . mRNA Export and Translation

IP6 stimulates mRNA export from the nucleus by interacting with Gle1 on the cytoplasmic side of the nuclear pore complex. This interaction allows Gle1 to stimulate the ATPase activity of its binding partner, the RNA Dbp5, and is essential for efficient mRNA export. The IP6-Gle1-Dbp5 interaction has also been shown to be required for the recruitment of termination factors to polysomes and proper translation termination. IP Structural Cofactors

Three independent structural studies have identified roles for IPs as structural cofactors. IP6 is bound in the core of the RNA-modifying enzyme ADAR2 and the plant auxin- sensing complex Tir1-Ask1. Additionally, the plant Jasmonate receptor binds to IP5 (not shown). In all cases, IP molecules appear to function as structural cofac- tors that have little to no “exchange” with bulk solvent. Other Roles This frame contains a list of additional biological roles in which IPs have been implicated. This list and the contents of the SnapShot are by no means exhaustive and are intended as a starting point for pursuing further reading.

References

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Michell, R.H. (2009). First came the link between phosphoinositides and Ca2+ signalling, and then a deluge of other phosphoinositide functions. Cell Calcium 45, 521–526.

Mikoshiba, K. (2007). IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. J. Neurochem. 102, 1426–1446.

Monserrate, J.P., and York, J.D. (2010). Inositol phosphate synthesis and the nuclear processes they affect. Curr. Opin. Cell Biol. 22, 365–373.

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1030.e1 Cell 143, December 10, 2010 ©2010 Elsevier Inc. DOI 10.1016/j.cell.2010.11.045