Regulation of Ins(3,4,5,6)P(4) signaling by a reversible kinase/phosphatase.
Regulation of Cl(-) channel conductance by Ins(3,4,5,6)P(4) provides receptor-dependent control over salt and fluid secretion, cell volume homeostasis, and electrical excitability of neurones and smooth muscle. Ignorance of how Ins(3,4,5,6)P(4) is synthesized has long hindered our understanding of this signaling pathway. We now show Ins(3,4,5,6)P(4) synthesis by Ins(1,3,4,5,6)P(5) 1-phosphatase activity by an enzyme previously characterized as an Ins(3,4,5,6)P(4) 1-kinase. Rationalization of these phenomena with a ligand binding model unveils Ins(1,3,4)P(3) as not simply an alternative kinase substrate, but also an activator of Ins(1,3,4,5,6)P(5) 1-phosphatase. Stable overexpression of the enzyme in epithelial monolayers verifies its physiological role in elevating Ins(3,4,5,6)P(4) levels and inhibiting secretion. It is exceptional for a single enzyme to catalyze two opposing signaling reactions (1-kinase/1-phosphatase) under physiological conditions. Reciprocal coordination of these opposing reactions offers an alternative to general doctrine that intracellular signals are regulated by integrating multiple, distinct phosphatases and kinases.
Ho
Melisa W Y
MW
Inositide Signaling Group, Laboratory of Signal Transduction and National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Yang
Xiaonian
X
Carew
Mark A
MA
Zhang
Tong
T
Hua
Len
L
Kwon
Yong-Uk
YU
Chung
Sung-Kee
SK
Adelt
Stephan
S
Vogel
Günter
G
Riley
Andrew M
AM
Potter
Barry V L
BV
Shears
Stephen B
SB
D002118:Calcium / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
D007295:Inositol Phosphates; D010744:Phosphoric Monoester Hydrolases; C053087:inositol-1,4-bisphosphate 1-phosphatase; D002118:Calcium