*Result*: A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment.
Title:
A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment.
Authors:
Anderson AP; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Kim S; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Melton AJ; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Ding X; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Zhang W; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Saltzman AB; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA., Malovannaya A; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA., Rasband MN; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Gao Y; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. yudong.gao@bcm.edu.
Source:
Nature communications [Nat Commun] 2025 Dec 03; Vol. 16 (1), pp. 10850. Date of Electronic Publication: 2025 Dec 03.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s):
Original Publication: [London] : Nature Pub. Group
MeSH Terms:
References:
Nat Rev Drug Discov. 2017 Nov;16(11):773-786. (PMID: 29026209)
Eur J Neurosci. 2011 Nov;34(10):1609-19. (PMID: 22103418)
Nat Methods. 2015 Jun;12(6):568-76. (PMID: 25915120)
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20055-60. (PMID: 18056633)
J Physiol. 2010 Jun 1;588(Pt 11):1823-7. (PMID: 20375141)
Nat Methods. 2020 Sep;17(9):869-870. (PMID: 32669682)
J Neurosci. 1997 Aug 15;17(16):6086-93. (PMID: 9236220)
J Neurosci. 1992 Oct;12(10):3743-52. (PMID: 1383476)
Eur J Med Genet. 2010 Sep-Oct;53(5):239-43. (PMID: 20601260)
Nat Methods. 2017 May;14(5):513-520. (PMID: 28394336)
Front Mol Neurosci. 2023 Dec 18;16:1269387. (PMID: 38169846)
Epilepsia. 2012 Jun;53 Suppl 1:134-41. (PMID: 22612818)
Nat Commun. 2023 Jul 27;14(1):4539. (PMID: 37500632)
Nucleic Acids Res. 2023 Jan 6;51(D1):D1038-D1045. (PMID: 36305825)
Elife. 2025 Feb 03;12:. (PMID: 39898808)
Mol Cell Proteomics. 2018 Nov;17(11):2270-2283. (PMID: 30093420)
Sci Adv. 2023 Jul 14;9(28):eadf7084. (PMID: 37450597)
J Cell Biol. 1997 May 5;137(3):703-14. (PMID: 9151675)
PLoS One. 2012;7(10):e48557. (PMID: 23119056)
BMC Biol. 2011 Sep 29;9:66. (PMID: 21958379)
Nat Biotechnol. 2012 Oct;30(10):918-20. (PMID: 23051804)
Nat Commun. 2020 Aug 13;11(1):4065. (PMID: 32792501)
BMC Genomics. 2008 Oct 16;9:488. (PMID: 18925949)
Front Neuroinform. 2022 Oct 3;16:957255. (PMID: 36221258)
Mol Cell Proteomics. 2015 Sep;14(9):2394-404. (PMID: 25987413)
Sci Adv. 2023 Sep 15;9(37):eadf3885. (PMID: 37713493)
Cell Genom. 2023 Jan 24;3(3):100250. (PMID: 36950384)
Pharmacogenomics J. 2007 Apr;7(2):123-32. (PMID: 16733521)
J Cell Biol. 2024 Oct 7;223(10):. (PMID: 39078369)
Mol Psychiatry. 2019 Sep;24(9):1248-1257. (PMID: 31089192)
J Neurosci. 2020 Apr 8;40(15):3119-3129. (PMID: 32144179)
Clin Proteomics. 2021 Dec 3;18(1):28. (PMID: 34861815)
J Neurosci. 2013 Apr 17;33(16):6950-63. (PMID: 23595753)
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2427288122. (PMID: 40294267)
J Biol Chem. 2015 Jul 3;290(27):16619-32. (PMID: 25998125)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Nat Neurosci. 2017 Aug;20(8):1172-1179. (PMID: 28671695)
J Cell Biol. 2011 Mar 7;192(5):813-24. (PMID: 21357749)
Nat Methods. 2007 Nov;4(11):923-5. (PMID: 17952086)
Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
PLoS One. 2012;7(10):e46683. (PMID: 23071613)
J Cell Sci. 2021 Jul 1;134(13):. (PMID: 34228795)
Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444. (PMID: 34791371)
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245. (PMID: 29762716)
Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835)
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1096-100. (PMID: 10655490)
Mol Cell Proteomics. 2020 Aug;19(8):1396-1408. (PMID: 32424025)
Front Genet. 2013 Nov 05;4:222. (PMID: 24204377)
Trends Biochem Sci. 2006 Aug;31(8):436-44. (PMID: 16828554)
J Proteome Res. 2021 Apr 2;20(4):1966-1971. (PMID: 33596079)
Nature. 2016 Sep 22;537(7621):508-514. (PMID: 27626380)
Bioinformatics. 2020 Apr 15;36(8):2628-2629. (PMID: 31882993)
Comput Biol Chem. 2008 Jun;32(3):215-7. (PMID: 18440872)
Cell. 2009 Oct 30;139(3):468-84. (PMID: 19879837)
J Biol Chem. 2003 Jul 4;278(27):24976-85. (PMID: 12716901)
Nature. 2023 Sep;621(7977):146-153. (PMID: 37648853)
Neuroscience. 2018 Jan 1;368:268-282. (PMID: 28739523)
Nat Neurosci. 2008 Feb;11(2):178-86. (PMID: 18204443)
Sci Rep. 2019 Sep 20;9(1):13662. (PMID: 31541176)
Cell Rep. 2022 Nov 22;41(8):111678. (PMID: 36417873)
Nucleic Acids Res. 2025 Jan 6;53(D1):D543-D553. (PMID: 39494541)
J Proteome Res. 2021 Jan 1;20(1):498-505. (PMID: 33332123)
Nat Commun. 2023 Oct 26;14(1):6797. (PMID: 37884508)
Science. 2016 Sep 9;353(6304):1123-9. (PMID: 27609886)
Mol Cell Proteomics. 2021;20:100077. (PMID: 33813065)
Nat Protoc. 2018 Jul;13(7):1632-1661. (PMID: 29988108)
Nat Commun. 2024 Aug 9;15(1):6801. (PMID: 39122707)
Ann N Y Acad Sci. 2018 May;1420(1):46-61. (PMID: 29749636)
Curr Opin Neurobiol. 2014 Aug;27:96-102. (PMID: 24705243)
Biochim Biophys Acta. 2015 Apr;1850(4):832-44. (PMID: 25615535)
J Proteome Res. 2019 Dec 6;18(12):4262-4272. (PMID: 31290668)
Nat Commun. 2023 Dec 11;14(1):8201. (PMID: 38081810)
Neuron. 2025 Mar 05;113(5):649-669. (PMID: 39947181)
J Biol Chem. 2008 Dec 26;283(52):36241-8. (PMID: 18940801)
Cell Mol Life Sci. 2013 Jan;70(1):105-20. (PMID: 22763697)
Semin Cell Dev Biol. 2011 Apr;22(2):160-5. (PMID: 20950703)
J Cell Biol. 2008 Dec 15;183(6):975-7. (PMID: 19075107)
Neuron. 2019 Nov 6;104(3):458-470.e5. (PMID: 31542321)
Methods Mol Biol. 2013;1053:283-305. (PMID: 23860660)
Protein Sci. 2023 Nov;32(11):e4792. (PMID: 37774136)
Neuron. 2007 Aug 16;55(4):633-47. (PMID: 17698015)
Neuron. 2019 Aug 21;103(4):583-597.e8. (PMID: 31272828)
J Cell Biol. 2008 Dec 15;183(6):1101-14. (PMID: 19064667)
Mol Neurobiol. 2024 Nov;61(11):8491-8517. (PMID: 38517617)
J Biol Chem. 2005 Jul 22;280(29):27375-82. (PMID: 15923182)
Curr Med Chem. 2003 Mar;10(6):505-24. (PMID: 12570695)
Genes Brain Behav. 2003 Oct;2(5):255-67. (PMID: 14606691)
Nat Protoc. 2019 Feb;14(2):379-414. (PMID: 30626963)
Eur J Neurosci. 2011 Nov;34(10):1609-19. (PMID: 22103418)
Nat Methods. 2015 Jun;12(6):568-76. (PMID: 25915120)
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20055-60. (PMID: 18056633)
J Physiol. 2010 Jun 1;588(Pt 11):1823-7. (PMID: 20375141)
Nat Methods. 2020 Sep;17(9):869-870. (PMID: 32669682)
J Neurosci. 1997 Aug 15;17(16):6086-93. (PMID: 9236220)
J Neurosci. 1992 Oct;12(10):3743-52. (PMID: 1383476)
Eur J Med Genet. 2010 Sep-Oct;53(5):239-43. (PMID: 20601260)
Nat Methods. 2017 May;14(5):513-520. (PMID: 28394336)
Front Mol Neurosci. 2023 Dec 18;16:1269387. (PMID: 38169846)
Epilepsia. 2012 Jun;53 Suppl 1:134-41. (PMID: 22612818)
Nat Commun. 2023 Jul 27;14(1):4539. (PMID: 37500632)
Nucleic Acids Res. 2023 Jan 6;51(D1):D1038-D1045. (PMID: 36305825)
Elife. 2025 Feb 03;12:. (PMID: 39898808)
Mol Cell Proteomics. 2018 Nov;17(11):2270-2283. (PMID: 30093420)
Sci Adv. 2023 Jul 14;9(28):eadf7084. (PMID: 37450597)
J Cell Biol. 1997 May 5;137(3):703-14. (PMID: 9151675)
PLoS One. 2012;7(10):e48557. (PMID: 23119056)
BMC Biol. 2011 Sep 29;9:66. (PMID: 21958379)
Nat Biotechnol. 2012 Oct;30(10):918-20. (PMID: 23051804)
Nat Commun. 2020 Aug 13;11(1):4065. (PMID: 32792501)
BMC Genomics. 2008 Oct 16;9:488. (PMID: 18925949)
Front Neuroinform. 2022 Oct 3;16:957255. (PMID: 36221258)
Mol Cell Proteomics. 2015 Sep;14(9):2394-404. (PMID: 25987413)
Sci Adv. 2023 Sep 15;9(37):eadf3885. (PMID: 37713493)
Cell Genom. 2023 Jan 24;3(3):100250. (PMID: 36950384)
Pharmacogenomics J. 2007 Apr;7(2):123-32. (PMID: 16733521)
J Cell Biol. 2024 Oct 7;223(10):. (PMID: 39078369)
Mol Psychiatry. 2019 Sep;24(9):1248-1257. (PMID: 31089192)
J Neurosci. 2020 Apr 8;40(15):3119-3129. (PMID: 32144179)
Clin Proteomics. 2021 Dec 3;18(1):28. (PMID: 34861815)
J Neurosci. 2013 Apr 17;33(16):6950-63. (PMID: 23595753)
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2427288122. (PMID: 40294267)
J Biol Chem. 2015 Jul 3;290(27):16619-32. (PMID: 25998125)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Nat Neurosci. 2017 Aug;20(8):1172-1179. (PMID: 28671695)
J Cell Biol. 2011 Mar 7;192(5):813-24. (PMID: 21357749)
Nat Methods. 2007 Nov;4(11):923-5. (PMID: 17952086)
Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
PLoS One. 2012;7(10):e46683. (PMID: 23071613)
J Cell Sci. 2021 Jul 1;134(13):. (PMID: 34228795)
Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444. (PMID: 34791371)
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245. (PMID: 29762716)
Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835)
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1096-100. (PMID: 10655490)
Mol Cell Proteomics. 2020 Aug;19(8):1396-1408. (PMID: 32424025)
Front Genet. 2013 Nov 05;4:222. (PMID: 24204377)
Trends Biochem Sci. 2006 Aug;31(8):436-44. (PMID: 16828554)
J Proteome Res. 2021 Apr 2;20(4):1966-1971. (PMID: 33596079)
Nature. 2016 Sep 22;537(7621):508-514. (PMID: 27626380)
Bioinformatics. 2020 Apr 15;36(8):2628-2629. (PMID: 31882993)
Comput Biol Chem. 2008 Jun;32(3):215-7. (PMID: 18440872)
Cell. 2009 Oct 30;139(3):468-84. (PMID: 19879837)
J Biol Chem. 2003 Jul 4;278(27):24976-85. (PMID: 12716901)
Nature. 2023 Sep;621(7977):146-153. (PMID: 37648853)
Neuroscience. 2018 Jan 1;368:268-282. (PMID: 28739523)
Nat Neurosci. 2008 Feb;11(2):178-86. (PMID: 18204443)
Sci Rep. 2019 Sep 20;9(1):13662. (PMID: 31541176)
Cell Rep. 2022 Nov 22;41(8):111678. (PMID: 36417873)
Nucleic Acids Res. 2025 Jan 6;53(D1):D543-D553. (PMID: 39494541)
J Proteome Res. 2021 Jan 1;20(1):498-505. (PMID: 33332123)
Nat Commun. 2023 Oct 26;14(1):6797. (PMID: 37884508)
Science. 2016 Sep 9;353(6304):1123-9. (PMID: 27609886)
Mol Cell Proteomics. 2021;20:100077. (PMID: 33813065)
Nat Protoc. 2018 Jul;13(7):1632-1661. (PMID: 29988108)
Nat Commun. 2024 Aug 9;15(1):6801. (PMID: 39122707)
Ann N Y Acad Sci. 2018 May;1420(1):46-61. (PMID: 29749636)
Curr Opin Neurobiol. 2014 Aug;27:96-102. (PMID: 24705243)
Biochim Biophys Acta. 2015 Apr;1850(4):832-44. (PMID: 25615535)
J Proteome Res. 2019 Dec 6;18(12):4262-4272. (PMID: 31290668)
Nat Commun. 2023 Dec 11;14(1):8201. (PMID: 38081810)
Neuron. 2025 Mar 05;113(5):649-669. (PMID: 39947181)
J Biol Chem. 2008 Dec 26;283(52):36241-8. (PMID: 18940801)
Cell Mol Life Sci. 2013 Jan;70(1):105-20. (PMID: 22763697)
Semin Cell Dev Biol. 2011 Apr;22(2):160-5. (PMID: 20950703)
J Cell Biol. 2008 Dec 15;183(6):975-7. (PMID: 19075107)
Neuron. 2019 Nov 6;104(3):458-470.e5. (PMID: 31542321)
Methods Mol Biol. 2013;1053:283-305. (PMID: 23860660)
Protein Sci. 2023 Nov;32(11):e4792. (PMID: 37774136)
Neuron. 2007 Aug 16;55(4):633-47. (PMID: 17698015)
Neuron. 2019 Aug 21;103(4):583-597.e8. (PMID: 31272828)
J Cell Biol. 2008 Dec 15;183(6):1101-14. (PMID: 19064667)
Mol Neurobiol. 2024 Nov;61(11):8491-8517. (PMID: 38517617)
J Biol Chem. 2005 Jul 22;280(29):27375-82. (PMID: 15923182)
Curr Med Chem. 2003 Mar;10(6):505-24. (PMID: 12570695)
Genes Brain Behav. 2003 Oct;2(5):255-67. (PMID: 14606691)
Nat Protoc. 2019 Feb;14(2):379-414. (PMID: 30626963)
Grant Information:
S10 OD026804 United States OD NIH HHS; R01 GM129325 United States GM NIGMS NIH HHS; P30 CA125123 United States CA NCI NIH HHS; R35 NS122073 United States NS NINDS NIH HHS; P50 HD103555 United States HD NICHD NIH HHS
Substance Nomenclature:
EC 3.1.3.16 (Protein Phosphatase 2)
0 (Kv1.2 Potassium Channel)
0 (Kv1.2 Potassium Channel)
Entry Date(s):
Date Created: 20251203 Date Completed: 20251203 Latest Revision: 20251207
Update Code:
20260130
PubMed Central ID:
PMC12675759
DOI:
10.1038/s41467-025-66120-0
PMID:
41339307
Database:
MEDLINE
*Further Information*
*Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in vitro development. With phosphoproteomics, we further reveal that the potassium channel Kv1.2 is one of the downstream targets that link Ppp2r2c activity to neuronal excitability. Together, these data provide a critical entry point for understanding the mechanisms of PP2A-mediated local phospho-regulation at the AIS.
(© 2025. The Author(s).)*
*Competing interests: Y.G. has a patent related to the HiUGE technology (U.S. Patent No. 12,325,855). The intellectual property was licensed to CasTag Biosciences. The remaining authors declare no competing interests.*