Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis.
Ryk is a transmembrane receptor tyrosine kinase (RTK). It functions as a receptor of Wnt proteins required for cell-fate determination, axon guidance, and neurite outgrowth in different organisms; however, the molecular mechanism of Ryk signaling is unknown. Here, we show that Ryk is cleaved, permitting the intracellular C-terminal fragment of Ryk to translocate to the nucleus in response to Wnt3 stimulation. We also show that the cleaved intracellular domain of Ryk is required for Wnt3-induced neuronal differentiation in vitro and in vivo. These results demonstrate an unexpected mechanism of signal transduction for Ryk as a Wnt receptor, in which the intracellular domain itself functions as the transducing molecule to bring extracellular signals from the cell surface into the nucleus, to regulate neural progenitor cell differentiation.
Lyu
Jungmook
J
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Yamamoto
Vicky
V
Lu
Wange
W
D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology*; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse; D053829:Amyloid Precursor Protein Secretases