Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation
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 Cdh...
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| Format: | Article |
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Society for Neuroscience
2010
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| Online Access: | http://hdl.handle.net/1721.1/55969 |
| _version_ | 1811095262189322240 |
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| author | Huynh, Mai Anh Stegmüller, Judith Litterman, Nadia Bonni, Azad |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Huynh, Mai Anh Stegmüller, Judith Litterman, Nadia Bonni, Azad |
| author_sort | Huynh, Mai Anh |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:14:17Z |
| format | Article |
| id | mit-1721.1/55969 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:14:17Z |
| publishDate | 2010 |
| publisher | Society for Neuroscience |
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| spelling | mit-1721.1/559692022-09-29T19:02:53Z Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation Huynh, Mai Anh Stegmüller, Judith Litterman, Nadia Bonni, Azad Harvard University--MIT Division of Health Sciences and Technology Huynh, Mai Anh Huynh, Mai Anh 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. 2010-06-25T17:35:28Z 2010-06-25T17:35:28Z 2009-04 2009-03 Article http://purl.org/eprint/type/JournalArticle 1529-2401 http://hdl.handle.net/1721.1/55969 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 en_US http://dx.doi.org/10.1523/jneurosci.5329-08.2009 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Huynh, Mai Anh Stegmüller, Judith Litterman, Nadia Bonni, Azad Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title | Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title_full | Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title_fullStr | Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title_full_unstemmed | Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title_short | Regulation of Cdh1-APC Function in Axon Growth by Cdh1 Phosphorylation |
| title_sort | regulation of cdh1 apc function in axon growth by cdh1 phosphorylation |
| url | http://hdl.handle.net/1721.1/55969 |
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