Regulation of Ins(3, 4, 5, 6)P4signaling by a reversible kinase/phosphatase

Melisa W.Y. Ho, Xiaonian Yang, Mark A. Carew, Tong Zhang, Len Hua, Yong Uk Kwon, Sung Kee Chung, Stephan Adelt, Günter Vogel, Andrew M. Riley, Barry V.L. Potter, Stephen B. Shears

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Regulation of Clchannel conductance by Ins(3, 4, 5, 6)P4provides receptor-dependent control over salt and fluid secretion [1], cell volume homeostasis [2], and electrical excitability of neurones and smooth muscle [3]. Ignorance of how Ins(3, 4, 5, 6)P4is synthesized has long hindered our understanding of this signaling pathway. We now show Ins(3, 4, 5, 6)P4synthesis by Ins(1, 3, 4, 5, 6)P51-phosphatase activity by an enzyme previously characterized [4] as an Ins(3, 4, 5, 6)P41-kinase. Rationalization of these phenomena with a ligand binding model unveils Ins(1, 3, 4)P3as not simply an alternative kinase substrate [4, 5], but also an activator of Ins(1, 3, 4, 5, 6)P51-phosphatase. Stable overexpression of the enzyme in epithelial monolayers verifies its physiological role in elevating Ins(3, 4, 5, 6)P4levels 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 [6].

Original languageEnglish
Pages (from-to)477-482
Number of pages6
JournalCurrent Biology
Issue number6
StatePublished - 2002

Bibliographical note

Funding Information:
We thank the Wellcome Trust for Programme Grant support (060554 to B.V.L.P.).


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