An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production.
Phospholipase C and several inositol polyphosphate kinase (IPK) activities generate a branched ensemble of inositol polyphosphate second messengers that regulate cellular signaling pathways in the nucleus and cytoplasm. Here, we report that mice deficient for Ipk2 (also known as inositol polyphosphate multikinase), an inositol trisphosphate and tetrakisphosphate 6/5/3-kinase active at several places in the inositol metabolic pathways, die around embryonic day 9.5 with multiple morphological defects, including abnormal folding of the neural tube. Metabolic analysis of Ipk2-deficient cells demonstrates that synthesis of the majority of inositol pentakisphosphate, hexakisphosphate and pyrophosphate species are disrupted, although the presence of 10% residual inositol hexakisphosphate indicates the existence of a minor alternative pathway. Agonist induced inositol tris- and bis-phosphate production and calcium release responses are present in homozygous mutant cells, indicating that the observed mouse phenotypes are a result of failure to produce higher inositol polyphosphates. Our data demonstrate that Ipk2 plays a major role in the synthesis of inositol polyphosphate messengers derived from inositol 1,4,5-trisphosphate and uncovers a role for their production in embryogenesis and normal development.
Frederick
Joshua P
JP
Department of Pharmacology, Howard Hughes Medical Institute, Duke University, Medical Center, Durham, NC 27710, USA.
Mattiske
Deidre
D
Wofford
Jessica A
JA
Megosh
Louis C
LC
Drake
Li Yin
LY
Chiou
Shean-Tai
ST
Hogan
Brigid L M
BL
York
John D
JD
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005816:Genetic Complementation Test; D005822:Genetic Vectors; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase