Canonical WNT signaling through the atypical receptor RYK

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Reaction [binding]
Homo sapiens
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RYK is an atypical receptor tyrosine kinase-like receptor that is required for craniofacial and skeletal development, axon guidance and neuronal differentiation. RYK has an extracellular WNT-binding WIF domain, a putative tetrabasic cleavage site, an intracellular PDZ domain and a cytosolic RTK-like catalytic site that is rendered inactive by a number of substitutions at conserved positions (reviewed in Fradkin et al, 2010; Keeble et al, 2006a). The WIF domain of RYK has been shown to interact with WNT1, 3, 3A and 5A and signaling through RYK is believed to contribute to both canonical and non-canonical WNT pathways (Lu et al, 2004; Keeble et al, 2006b; Liu et al, 2005; Macheda et al, 2012; Schmitt et al, 2006; reviewed in Keeble et al, 2006a).

Expression of a beta-catenin-dependent reporter gene has been demonstrated after RYK-binding by WNT1 and WNT3A, however the details of downstream signaling remain to be clarified (Lu et al, 2004; Berndt et al, 2011). Signaling through RYK may occur in the context of a RYK-FZD co-receptor and appears to involve the recruitment of DVL (Lu et al, 2004). The E3 ligase Mindbomb (MIB1) was also identified as a RYK-interacting protein that contributes to canonical WNT signaling, possibly by regulating the levels of RYK at the cell surface (Berndt et al, 2011). Finally, RYK has been shown to be cleaved by gamma-secretase in response to WNT3, liberating a intracellular domain (ICD) that translocates to the nucleus and that is required for neuronal differentitation (Lyu et al, 2008). The significance of these findings is not yet fully clear.
Literature References
PubMed ID Title Journal Year
16280981 Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping

Shi, J, Schmitt, AM, Zou, Y, Lu, CC, Wolf, AM, King, LA

Nature 2006
16723543 The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum

Seaman, C, Halford, MM, Anderson, RB, Stacker, SA, Keeble, TR, Macheda, M, Kee, N, Cooper, HM

J. Neurosci. 2006
19000841 Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis

Lu, W, Lyu, J, Yamamoto, V

Dev. Cell 2008
22773843 The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling

Lieschke, GJ, Kugathasan, K, Halford, MM, Sun, WW, Zhang, YF, Stacker, SA, Jacques, BE, Bower, NI, Hogan, BM, Dabdoub, A, Macheda, ML

J. Biol. Chem. 2012
16116452 Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract

Shi, J, Zou, Y, Lu, CC, Song, XJ, Liu, Y, Lyuksyutova, AI, Wang, ZB

Nat. Neurosci. 2005
15454084 Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth

Ortega, B, Baltimore, D, Lu, W, Yamamoto, V

Cell 2004
20004982 Ryks: new partners for Wnts in the developing and regenerating nervous system

Fradkin, LG, Noordermeer, JN, Dura, JM

Trends Neurosci. 2010
21875946 Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/?-catenin signaling

Berndt, JD, Tang, L, Yang, P, Aoyagi, A, Anastas, JN, Moon, RT

J. Cell Biol. 2011
16971168 Ryk: a novel Wnt receptor regulating axon pathfinding

Keeble, TR, Cooper, HM

Int. J. Biochem. Cell Biol. 2006
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