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DYRK1B regulates Hedgehog-induced microtubule acetylation

  • Rajeev Singh
  • Philipp Simon Holz
  • Katrin Roth
  • Anna Hupfer
  • Wolfgang Meissner
  • Rolf Müller
  • Malte Buchholz
  • Thomas M. Gress
  • Hans-Peter Elsässer
  • Ralf Jacob
  • Matthias Lauth
Original Article
  • 97 Downloads

Abstract

The posttranslational modification (PTM) of tubulin subunits is important for the physiological functions of the microtubule (MT) cytoskeleton. Although major advances have been made in the identification of enzymes carrying out MT-PTMs, little knowledge is available on how intercellular signaling molecules and their associated pathways regulate MT-PTM-dependent processes inside signal-receiving cells. Here we show that Hedgehog (Hh) signaling, a paradigmatic intercellular signaling system, affects the MT acetylation state in mammalian cells. Mechanistically, Hh pathway activity increases the levels of the MT-associated DYRK1B kinase, resulting in the inhibition of GSK3β through phosphorylation of Serine 9 and the subsequent suppression of HDAC6 enzyme activity. Since HDAC6 represents a major tubulin deacetylase, its inhibition increases the levels of acetylated MTs. Through the activation of DYRK1B, Hh signaling facilitates MT-dependent processes such as intracellular mitochondrial transport, mesenchymal cell polarization or directed cell migration. Taken together, we provide evidence that intercellular communication through Hh signals can regulate the MT cytoskeleton and contribute to MT-dependent processes by affecting the level of tubulin acetylation.

Keywords

Hedgehog SHH DYRK1B HDAC6 GSK3β Microtubules Acetylation Organelle transport Cell migration 

Abbreviations

DYRK1B

Dual specificity-regulated kinase 1B (a.k.a. MIRK)

Hh

Hedgehog

SHH

Sonic Hedgehog

GLI1

Glioma-associated oncogene 1

GSK3β

Glycogen synthase kinase 3 beta

HDAC6

Histone deacetylase 6

MT

Microtubule

AcTub

Acetylated α-tubulin

SAG

Smoothened agonist

SANT

Smoothened antagonist

MTOC

Microtubule (MT) organizing center

Notes

Acknowledgements

This work was supported by grants obtained from the German Research Society (DFG-KFO325 and DFG-LA2829/9-1), the Behring-Röntgen Foundation and the University Hospital Giessen-Marburg (UKGM).

Compliance with ethical standards

Conflict of interest

No competing interest declared.

Supplementary material

18_2018_2942_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1510 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Rajeev Singh
    • 1
  • Philipp Simon Holz
    • 1
  • Katrin Roth
    • 2
  • Anna Hupfer
    • 1
  • Wolfgang Meissner
    • 1
  • Rolf Müller
    • 1
  • Malte Buchholz
    • 3
  • Thomas M. Gress
    • 3
  • Hans-Peter Elsässer
    • 4
  • Ralf Jacob
    • 4
  • Matthias Lauth
    • 1
  1. 1.Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor- and Immune Biology (ZTI)Philipps UniversityMarburgGermany
  2. 2.Imaging Core Facility, Center for Tumor- and Immune Biology (ZTI)Philipps UniversityMarburgGermany
  3. 3.Clinic for Gastroenterology, Endocrinology, Metabolism and InfectiologyPhilipps UniversityMarburgGermany
  4. 4.Institute of Cytobiology and CytopathologyPhilipps UniversityMarburgGermany

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