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A necessary component of Wnt signaling occurs in a subcellular compartment distinct …

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- A critical role for endocytosis in Wnt signaling

The Wnt signaling pathway is largely conserved from Drosophila to humans and has been shown to regulate diverse embryonic processes including axis specification and organogenesis. Wnt signaling events have also been implicated in a number of cancers, bone density phenotypes, and neurological conditions in adulthood [1,2]. Wnts are a family of secreted proteins which are glycosylated and lipidated, exerting their predominant physiological effects through receptors of the Frizzled and Arrow/low-density lipoprotein (LDL) receptor-related protein 5/6 (LRP5/6) families. Frizzleds are seven transmembrane domain-containing proteins that are the primary receptors for Wnts, whereas LRPs (specifically LRP5 and LRP6) are single pass membrane proteins that serve as co-receptors. In the "canonical Wnt pathway," Wnts bind to their cognate receptors and stimulate the cytoplasmic stabilization of β-catenin through the inhibition of an elaborate degradation complex consisting of APC, Axin, and glycogen synthase kinase 3 (GSK3). Stabilized β-catenin translocates to the nucleus where it interacts with transcriptional regulators of the T cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins to mediate transcription of Wnt target genes [2]. Recently, there has been evidence suggesting that heterotrimeric G proteins may have a role in Wnt signaling [3,4].

While Wnts, their receptors, and numerous downstream components have been identified through genetic and biochemical approaches, the upstream molecular events occurring directly after Frizzled activation have not been well-characterized. Importantly, it has not been established whether the majority of Wnt signal transduction occurs at the plasma membrane or on some intracellular organelle. There have been very few studies examining Wnt trafficking to intracellular compartments, and those demonstrating internalization of Wg/Frizzled2 in Drosophila [5] and Wnt5A/Frizzled4 in mammalian cells [6] have primarily suggested a role for Wnt trafficking in degradation of the ligand/receptor complex following signal transduction. While endocytosis of ligand/receptor pairs has traditionally been considered a longer-term mechanism for termination of a signaling pathway, recent evidence with receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) has suggested that internalization facilitates certain aspects of cellular signaling. Indeed, both epidermal growth factor- and β-adrenergic receptor-mediated activation of mitogen-activated protein kinase have been demonstrated to be dependent upon clathrin-mediated internalization [7,8]. However, Wnt signaling requires two kinds of receptors, the Frizzleds and the LRPs, and it would therefore be important to establish the cellular compartment where signaling takes place.

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