Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation
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Huynh-2009-Regulation of Cdh1-A.pdf
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Author(s)
Huynh, Mai Anh
Stegmüller, Judith
Litterman, Nadia
Bonni, Azad
Date Issued
April 2009
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Citation
Huynh, Mai Anh et al. “Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation.” J. Neurosci. 29.13 (2009): 4322-4327. © 2009 The Society for Neuroscience
Version
Final published version
Abstract
The ubiquitin ligase Cdh1–anaphase promoting complex (Cdh1–APC) plays a key role in the control of axonal morphogenesis in the mammalian brain, but the mechanisms that regulate neuronal Cdh1–APC function remain incompletely understood. Here, we have characterized the effect of phosphorylation of Cdh1 at cyclin-dependent kinase (Cdk) sites on Cdh1–APC function in neurons. We replaced nine conserved sites of Cdk-induced Cdh1 phosphorylation with alanine (9A) or aspartate (9D) to mimic hypo- or hyper-phosphorylation, respectively. We found that the 9A mutation triggered the proteasome-dependent degradation of Cdh1, and conversely the 9D mutation stabilized Cdh1 in neuronal cells. However, the phosphomimic 9D Cdh1 protein failed to associate with the APC core protein Cdc27. In addition, whereas wild-type and 9A Cdh1 predominantly localized to the nucleus, the 9D Cdh1 protein accumulated in the cytoplasm in neurons. Importantly, in contrast to wild-type and 9A Cdh1, the 9D Cdh1 mutant failed to inhibit axon growth in primary cerebellar granule neurons. Collectively, our results suggest that phosphorylation of neuronal Cdh1 at Cdk sites triggers the stabilization of an inactive form of Cdh1 that accumulates in the cytoplasm, leading to the inhibition of Cdh1–APC function in the control of axon growth. Thus, phosphorylation of Cdh1 may represent a critical mechanism regulating Cdh1–APC function in the nervous system.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1523/jneurosci.5329-08.2009
