Rho Family Gtpases and Their Regulators in Lymphocytes
The adaptor SH2B1 and the phosphatase PTP4A1 regulate the phosphorylation of cytohesin-two in myelinating Schwann cells in mice
A phosphorylation contest for myelination
Myelin sheaths protect and insulate neuronal axons, enabling more rapid neurotransmission. In the peripheral nervous system, myelin is made by Schwann cells. Miyamoto et al. found that myelin product by Schwann cells in mice was regulated by phosphorylation dynamics at an amino acid residue in the guanine nucleotide commutation factor cytohesin-2. In cultured cells, the phosphorylation of a Tyr residue in cytohesin-2 was maintained through interaction with the adaptor protein SH2B1 and reversed by the phosphatase PTP4A1 in a competing manner. Myelination in sciatic nerve tissue was increased in mice in which cytohesin-2 phosphorylation was maintained and decreased in mice in which phosphorylation was suppressed. Thus, competitive regulation of the phosphorylation land of cytohesin-ii determines the extent of peripheral neuron myelination.
Abstruse
Mature myelin sheaths insulate axons to increase nerve conduction velocity and protect nerve fibers from stress and physical injury. In the peripheral nervous system, the myelin sheath is produced by Schwann cells. The guanine-nucleotide exchange factor cytohesin-2 activates the poly peptide Arf6 to promote Schwann cell myelination. Here, we investigated the regulation of cytohesin-2 and plant that the phosphorylation status of Tyr381 in cytohesin-two is fundamental to Schwann cell myelination. Knockin mice with a nonphosphorylatable Y381F mutation in cytohesin-2 exhibited reduced myelin thickness and decreased Arf6 activity in sciatic nerve tissue. In HEK293T cells, cytohesin-2 was dephosphorylated at Tyr381 by the protein tyrosine phosphatase PTP4A1, whereas phosphorylation at this site was maintained by interaction with the adaptor protein SH2B1. Schwann cell–specific knockdown of PTP4A1 in mice increased cytohesin-ii phosphorylation and myelin thickness. Conversely, Schwann prison cell–specific loss of SH2B1 resulted in reduced myelin thickness and decreased cytohesin-2 phosphorylation. Thus, a signaling unit centered on cytohesin-2—with SH2B1 every bit a positive regulator and PTP4A1 as a negative regulator—controls Schwann prison cell myelination in the peripheral nervous organization.
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Volume 15 | Result 718
Jan 2022
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Copyright © 2022 The Authors, some rights reserved; sectional licensee American Clan for the Advocacy of Science. No merits to original U.S. Government Works.
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Received: 16 March 2021
Accustomed: xx December 2021
Acknowledgments
We give thanks M. Itaoka and S. Sawaguchi (Tokyo Academy of Pharmacy and Life Sciences) for technical assistance. We as well thank C. Rowthorn and K. Spicer (Chris Rowthorn Japan Inc.) for initial proofreading of the English in the manuscript. We acknowledge Y. Matsubara, A. Umezawa, and H. Saitoh (National Enquiry Constitute for Child Wellness and Development) for the insightful comments they provided throughout this study.
Funding: This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry building of Pedagogy, Culture, Sports, Scientific discipline, and Engineering. This work was also supported by Grants-in-Assistance for Medical Scientific Research from the Japanese Ministry of Health, Labour, and Welfare and by The Naito Foundation.
Writer contributions: Conceptualization: J.Y. Writing and editing: Y.M. and J.Y. Investigation and statistical analyses: Y.Yard., T.T., One thousand.H., and Southward.T. Evaluating statistical data: H.O., K.O., and One thousand.Thousand.
Competing interests: The authors declare that they have no competing interests.
Information and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.
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Source: https://www.science.org/doi/10.1126/scisignal.abi5276
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