ERK2-mediated phosphorylation of Par3 regulates neuronal polarization.
Open accessAbstract
Axon formation is one of the most important events in neuronal polarization and is regulated by signaling molecules involved in cytoskeletal rearrangement and protein transport. We previously found that Partition-defective 3 (Par3) is associated with KIF3A (kinesin-2) and is transported into the nascent axon in a KIF3A-dependent fashion. Par3 interacts with the Rac-specific guanine nucleotide-exchange factors (GEFs) Tiam1/2, which activate Rac1, and participates in axon formation in cultured hippocampal neurons. However, the regulatory mechanism of the Par3-KIF3A interaction is poorly understood, and the role of Par3 in neuronal polarization in vivo remains elusive. Here, we found that extracellular signal-regulated kinase 2 (ERK2) directly interacts with Par3, that ERK2 phosphorylates Par3 at Ser-1116, and that the phosphorylated Par3 accumulates at the axonal tips in a manner dependent upon ERK2 activity. The phosphorylation of Par3 by ERK2 inhibited the interaction of Par3 with KIF3A but not with the other Par3 partners, including Par6 and aPKC. The phosphomimic mutant of Par3 (Par3-S1116D) showed less binding activity with the KIF3s and slower transport in the axons. The knockdown of Par3 by RNA interference impaired neuronal polarization, which was rescued with RNAi-resistant Par3, but not with the phosphomimic Par3 mutant, in cultured rat hippocampal neurons and mouse cortical projection neurons in vivo. These results suggest that ERK2 phosphorylates Par3 and inhibits its binding with KIF3A, thereby controlling Par3 transport and neuronal polarity.
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During the establishment of polarity, kinesin-2 transports Par3 into the axon where it is released after phosphorylation by Erk2.
“During the establishment of polarity, kinesin-2 transports Par3 into the axon where it is released after phosphorylation by Erk2 (Funahashi et al., 2013).”
From Rassf5 and Ndr kinases act in a novel pathway regulating neuronal polarity through Par3 phosphorylation (2014) · cites this paper as Funahashi et al., 2013
The passage on Par3 transport says kinesin-2 (KIF3A) carries Par3 toward the tip of a developing axon. The Methods and Results passage reports that ERK2 phosphorylates Par3 in the distal axon and weakens its binding to KIF3A. The Conclusion discusses unloading as a proposed mechanism, but does not establish that Par3 is released there after phosphorylation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDisruption of Par3 localization by interfering with the kinesin-2-dependent transport of Par3 causes polarity defects in hippocampal neurons, showing that the restricted localization of Par3 to the axon is essential for neuronal polarity.
“Disruption of Par3 localization by interfering with the kinesin-2-dependent transport of Par3 causes polarity defects in hippocampal neurons, showing that the restricted localization of Par3 to the axon is essential for neuronal polarity (Funahashi et al., 2013; Nishimura et al., 2004).”
From Rassf5 and Ndr kinases act in a novel pathway regulating neuronal polarity through Par3 phosphorylation (2014) · cites this paper as Funahashi et al., 2013
The Ndr phosphorylation sites in Par3 (Ser383 and Ser1196) are novel and distinct from the sites for Aurora A, ROCK and Erk2 that regulate Par3 function in neuronal polarity.
“The Ndr phosphorylation sites in Par3 are novel and distinct from the sites for Aurora A, ROCK and Erk2 that regulate its function in neuronal polarity (Chen et al., 2006; Funahashi et al., 2013; Khazaei and Püschel, 2009; Nakayama et al., 2008).”
From Rassf5 and Ndr kinases act in a novel pathway regulating neuronal polarity through Par3 phosphorylation (2014) · cites this paper as Funahashi et al., 2013
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Cites
Kinesin superfamily motor proteins and intracellular transport
Hirokawa, N., Noda, Y., Tanaka, Y., & Niwa, S. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2774 · Cited by 1,859 · cited 1× · see citing works
“The loading and unloading of cargo, such as Par3 and specific vesicles on kinesins, seem to be tightly regulated to ensure proper axon formation and neuronal function (Arimura and Kaibuchi, 2007; Hirokawa et al., 2009).”
BackgroundHippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity
Shi, S.-H., Jan, L. Y., & Jan, Y.-N. (2003) · Cell · doi:10.1016/s0092-8674(02)01249-7 · Cited by 600 · see citing works
The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity.
Schwamborn, J. C., & Püschel, A. W. (2004) · Nature Neuroscience · doi:10.1038/nn1295 · Cited by 385 · see citing works
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Ng, C. K. Y., Dazert, E., Boldanova, T., Coto-Llerena, M., Nuciforo, S., Ercan, C., Suslov, A., Meier, M.-A., Bock, T., Schmidt, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29960-8 · Cited by 165 · see citing works
Yang, R., Kong, E., Jin, J., Hergovich, A., & Püschel, A. W. (2014) · Journal of Cell Science · doi:10.1242/jcs.146696 · Cited by 25 · see citing works
- Authors
- Funahashi, Y., Namba, T., Fujisue, S., Itoh, N., Nakamuta, S., Kato, K., Shimada, A., Xu, C., Shan, W., Nishioka, T., & Kaibuchi, K.
- Affiliations
- Japan Science and Technology Agency (JP)
- Nagoya University (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-08-14
- Volume
- 33
- Issue
- 33
- Pages
- 13270-13285
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6705157
- OpenAlex
- W2006536157
- Cited by
- 38
- References
- 3
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 4 · 2018: 1 · 2017: 2 · 2015: 6 · 2014: 5
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Nagoya University Repository (NAGOYA Repository) (submittedVersion, other-oa)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (CREST)
- Japan Society for the Promotion of Science (221S0003, CREST)
- Japan Science and Technology Agency (CREST)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Par3, ERK2, neuronal polarity, axon formation, KIF3A, kinesin-2, axonal transport, protein phosphorylation, Rac1, Par6, atypical protein kinase C, hippocampal neurons, cortical projection neurons
- MeSH terms
- Animals, Carrier Proteins, Chlorocebus aethiops, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Mice, Inbred ICR, Nerve Tissue Proteins, Neurons, Phosphorylation, Transfection, Xenopus, Kinesins, Cell Polarity, Rats, Wistar, COS Cells, Mitogen-Activated Protein Kinase 1, Protein Transport, RNA, Small Interfering, Immunoprecipitation, Mice, Rats
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