Wnt Signaling Pathways Mediated by Ca 2+ and Cyclic GMP

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 β-catenin, but instead operate largely in a β-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 Ca 2+ concentration. Characterization of the proximal signaling revealed that Wnt-5A activates Frizzled-2, G proteins, and the G protein effector phospholipase Cβ (PLCβ), stimulating an accumulation of intracellular inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). Elevation of IP 3 leads to intracellular Ca 2+ release and subsequent activation of Ca 2+ -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, Ca 2+ , and cyclic GMP: Visualizing Frizzled functions. Science 300 , 1529-1530 (2003). [ Abstract ] [ Full Text ]