Wnt Signaling Pathways Mediated by Ca²⁺ and Cyclic GMP

Hsien-yu Wang^1* and Craig C. Malbon²

¹Department of Physiology & Biophysics, Health Science Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
²Department of Pharmacology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.

Abstract: Wnts are secreted glycoprotein ligands that bind to and signal through Frizzleds, which are receptors of the seven-transmembrane, heterotrimeric guanine nucleotide-binding protein (G protein) -coupled receptor family. Wnt-Frizzled signaling is critical in a wide spectrum of developmental roles including cell fate, polarity, differentiation, migration, and proliferation. The Wnt family in mammals includes nearly 20 members and some, such as Wnt-4, -5A, and -11, activate Frizzleds that do not normally lead to the stabilization of intracellular concentrations of ß-catenin, but instead operate largely in a ß-catenin-independent manner. Studies (first in Xenopus and zebrafish, and later in mammalian cells) demonstrated that activation of Frizzled-2 by Wnt-5A stimulated the phosphatidylinositol pathway and an increase in intracellular Ca²⁺ concentration. Characterization of the proximal signaling revealed that Wnt-5A activates Frizzled-2, G proteins, and the G protein effector phospholipase Cß (PLCß), stimulating an accumulation of intracellular inositol trisphosphate (IP₃) and diacylglycerol (DAG). Elevation of IP₃ leads to intracellular Ca²⁺ release and subsequent activation of Ca²⁺-calmodulin-dependent protein kinase II, as well as the calcium-sensitive protein phosphatase calcineurin. Elevation of intracellular DAG activates protein kinase C (PKC). These pathways allow Wnt-5A to regulate the activity of transcription factors that control those genes activated in response to Wnt-5A. The G protein G_t2 (known also as transducin2) and its effector, guanosine 3',5'-monophosphate (cyclic GMP) phosphodiesterase, are activated also by the Wnt-Frizzled-2 pathway. The sharp decline in intracellular cyclic GMP, which can be blocked by selective cyclic GMP phosphodiesterase inhibitors, is required for Wnt-5A stimulation of primitive endoderm formation in mouse totipotent teratocarcinoma cells and Wnt-5A stimulation of early development in zebrafish embryos.

Science Viewpoint

H.-y. Wang, C. C. Malbon, Wnt signaling, Ca²⁺, and cyclic GMP: Visualizing Frizzled functions. Science 300, 1529-1530 (2003). [Abstract] [Full Text]

* Corresponding author. E-mail, wangh{at}pharm.sunysb.edu