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Research

Insulin Induces Microtubule Stabilization and Regulates the Microtubule Plus-end Tracking Protein Network in Adipocytes

View ORCID ProfileSara S. Parker, James Krantz, Eun-A Kwak, Natalie K. Barker, Chris G. Deer, Nam Y. Lee, Ghassan Mouneimne and View ORCID ProfilePaul R. Langlais  Correspondence email
Molecular & Cellular Proteomics July 1, 2019, First published on April 24, 2019, 18 (7) 1363-1381; https://doi.org/10.1074/mcp.RA119.001450
Sara S. Parker
From the ‡Department of Cellular & Molecular Medicine,
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James Krantz
§Department of Medicine, Division of Endocrinology,
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Eun-A Kwak
¶Department of Pharmacology,
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Natalie K. Barker
§Department of Medicine, Division of Endocrinology,
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Chris G. Deer
**University of Arizona Research Computing, University of Arizona, Tucson, Arizona 85721
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Nam Y. Lee
¶Department of Pharmacology, ‖Department of Chemistry & Biochemistry, University of Arizona College of Medicine, Tucson, Arizona 85721;
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Ghassan Mouneimne
From the ‡Department of Cellular & Molecular Medicine,
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Paul R. Langlais
§Department of Medicine, Division of Endocrinology,
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  • ORCID record for Paul R. Langlais
  • For correspondence: langlais@deptofmed.arizona.edu
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Graphical Abstract

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Highlights

  • Insulin Affects the Phosphorylation of G2L1, MARK2, CLIP2, EB1, AGAP3, and CKAP5.

  • Insulin Increases CLASP2 +TIP Density and Decreases CLASP2 +TIP Velocity.

  • Insulin Stimulates CLASP2 and G2L1 Trailing Along Microtubules.

  • Insulin Stimulates α-Tubulin Acetylation at Lysine 40 and Microtubule Stabilization.

Abstract

Insulin-stimulated glucose uptake is known to involve microtubules, although the function of microtubules and the microtubule-regulating proteins involved in insulin action are poorly understood. CLASP2, a plus-end tracking microtubule-associated protein (+TIP) that controls microtubule dynamics, was recently implicated as the first +TIP associated with insulin-regulated glucose uptake. Here, using protein-specific targeted quantitative phosphoproteomics within 3T3-L1 adipocytes, we discovered that insulin regulates phosphorylation of the CLASP2 network members G2L1, MARK2, CLIP2, AGAP3, and CKAP5 as well as EB1, revealing the existence of a previously unknown microtubule-associated protein system that responds to insulin. To further investigate, G2L1 interactome studies within 3T3-L1 adipocytes revealed that G2L1 coimmunoprecipitates CLASP2 and CLIP2 as well as the master integrators of +TIP assembly, the end binding (EB) proteins. Live-cell total internal reflection fluorescence microscopy in adipocytes revealed G2L1 and CLASP2 colocalize on microtubule plus-ends. We found that although insulin increases the number of CLASP2-containing plus-ends, insulin treatment simultaneously decreases CLASP2-containing plus-end velocity. In addition, we discovered that insulin stimulates redistribution of CLASP2 and G2L1 from exclusive plus-end tracking to “trailing” behind the growing tip of the microtubule. Insulin treatment increases α-tubulin Lysine 40 acetylation, a mechanism that was observed to be regulated by a counterbalance between GSK3 and mTOR, and led to microtubule stabilization. Our studies introduce insulin-stimulated microtubule stabilization and plus-end trailing of +TIPs as new modes of insulin action and reveal the likelihood that a network of microtubule-associated proteins synergize to coordinate insulin-regulated microtubule dynamics.

  • Affinity proteomics
  • Label-free quantification
  • Phosphorylation
  • Protein-Protein Interactions*
  • Quantification
  • CLASP2
  • G2L1
  • Insulin
  • Interactome
  • Microtubules

Footnotes

  • ↵§§ Co-first author.

  • Author contributions: S.S.P., J.K., N.Y.L., G.M., and P.R.L. designed research; S.S.P., J.K., E.-A.K., N.K.B., and P.R.L. performed research; S.S.P., J.K., N.Y.L., G.M., and P.R.L. contributed new reagents/analytic tools; S.S.P., J.K., E.-A.K., C.G.D., N.Y.L., G.M., and P.R.L. analyzed data; S.S.P., J.K., C.G.D., N.Y.L., and P.R.L. wrote the paper.

  • ↵* Imaris at the University of Arizona is supported by a TRIF Space Exploration and Optical Sciences (TRIF-SEOS) grant.

  • ↵Embedded Image This article contains supplemental material.

  • Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Received March 19, 2019.
  • © 2019 Parker et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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Insulin Induces Microtubule Stabilization and Regulates the Microtubule Plus-end Tracking Protein Network in Adipocytes
Sara S. Parker, James Krantz, Eun-A Kwak, Natalie K. Barker, Chris G. Deer, Nam Y. Lee, Ghassan Mouneimne, Paul R. Langlais
Molecular & Cellular Proteomics July 1, 2019, First published on April 24, 2019, 18 (7) 1363-1381; DOI: 10.1074/mcp.RA119.001450

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Insulin Induces Microtubule Stabilization and Regulates the Microtubule Plus-end Tracking Protein Network in Adipocytes
Sara S. Parker, James Krantz, Eun-A Kwak, Natalie K. Barker, Chris G. Deer, Nam Y. Lee, Ghassan Mouneimne, Paul R. Langlais
Molecular & Cellular Proteomics July 1, 2019, First published on April 24, 2019, 18 (7) 1363-1381; DOI: 10.1074/mcp.RA119.001450
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Molecular & Cellular Proteomics: 18 (7)
Molecular & Cellular Proteomics
Vol. 18, Issue 7
1 Jul 2019
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