Cdc37 Regulates Ryk Signaling by Stabilizing the Cleaved Ryk Intracellular Domain

The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2009; 284(19):12940-8. DOI: 10.1074/jbc.M900207200
Source: PubMed


Ryk is a Wnt receptor that plays an important role in neurogenesis, neurite outgrowth, and axon guidance. We have reported
that the Ryk receptor is cleaved by γ-secretase and that its intracellular domain (ICD) translocates to the nucleus upon Wnt
stimulation. Cleavage of Ryk and its ICD is important for the function of Ryk in neurogenesis. However, the question of how
the Ryk ICD is stabilized and translocated into the nucleus remains unanswered. Here, we show that the Ryk ICD undergoes ubiquitination
and proteasomal degradation. We have identified Cdc37, a subunit of the molecular chaperone Hsp90 complex, as a Ryk ICD-interacting
protein that inhibits proteasomal degradation of the Ryk ICD. Overexpression of Cdc37 increases Ryk ICD levels and promotes
its nuclear localization, whereas Cdc37 knockdown reduces Ryk ICD stability. Furthermore, we have discovered that the Cdc37-Ryk
ICD complex is disrupted during neural differentiation of embryonic stem cells, resulting in Ryk ICD degradation. These results
suggest that Cdc37 plays an essential role in regulating Ryk ICD stability and therefore in Ryk-mediated signal transduction.

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    ABSTRACT: Conserved Ryk transmembrane proteins, tyrosine kinase-related Wnt receptors, are important during neurogenesis, axon guidance and synaptogenesis. Here, we review the increasingly complex biology of the Wnt/Ryk pathway, emphasizing the mechanisms by which Ryks transduce or sometimes block the Wnt signal. Recent studies reveal that Wnts signal through Ryk via multiple mechanisms, including nuclear translocation of their intracellular domains and pathways employing Src Family Kinases and members of the canonical Wnt pathway. We also discuss reports indicating that Wnt/Ryk axon guidance roles are evolutionarily conserved and Wnt/Ryk interactions are required for motoneuron target selection and synaptogenesis at the neuromuscular junction. Recent findings that injury-induced Wnt/Ryk pathway activation inhibits axon regeneration underscore the importance of further understanding this novel pathway.
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