Further Development 4.12: Endosome Internalization:Morphogen Gradients Can Be Created by Literally Passing from One Cell to Another

Cell-to-Cell Communication: Mechanisms of Morphogenesis

The type and number of receptors that a cell displays at its cell surface represent its potential for response. Endocytosis is one mechanism used to eliminate a receptor at the membrane. Recent studies are revealing that internalization of ligand-receptor complexes into membrane-bound vesicles called endosomes is a common mechanism in paracrine signaling. When Wnt binds to its receptors, the β-catenin destruction complex binds to the receptor, and the entire complex (including the receptor and its bound Wnt) is internalized in endosomes (Figure 1; Taelman et al. 2010; Niehrs 2012). This process removes the complex, targets it for degradation, and enables the survival of β-catenin. The internalization of the signaling complex appears to be critical for the accumulation of β-catenin, and proteins that aid in this endocytosis (such as R-spondins; see Figure 4.26) make the Wnt pathway more efficient (Ohkawara et al. 2011). Similarly, Hedgehog-Patched complexes and FGF-FGFR complexes are also internalized in endosomes and targeted for degradation, a process that is required for proper limb development (Briscoe and Thérond 2013; Handschuh et al. 2014; Hsia et al. 2015).

Figure 1 A Wnt pathway: packaging the β-catenin destruction apparatus into endosomes. A major mechanism for separating β-catenin from enzymes that would otherwise destroy it is to package the complex in membrane-bound vesicles called endosomes. When Wnt binds to Frizzled, Frizzled can bind the destruction complex (DC); the entire complex (including the bound Wnt and its receptor) is internalized, allowing β-catenin to accumulate rather than being degraded. (After Taelman et al. 2010.)

Literature Cited

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Handschuh, K. and 21 others. 2014. ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling. Cell Rep. 9: 674–687.
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Hsia, E. Y., Y. Gui and X. Zheng. 2015. Regulation of Hedgehog signaling by ubiquitination. Front. Biol. 10: 203–220.
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Niehrs, C. 2012. The complex world of Wnt receptor signalling. Nat. Rev. Mol. Cell Biol. 13: 767–779.
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Ohkawara, B., A. Glinka and C. Niehrs. 2011. Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Dev. Cell 20: 303–314.
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Taelman, V. F., R. Dobrowolski, J. L. Plouhinec, L. C. Fuentealba, P. P. Vorwald, I. Gumper, D. D. Sabatini and E. M. De Robertis. 2010. Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143: 1136–1148.
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