The GPCR adaptor protein Norbin regulates S1PR1 trafficking and the morphology, cell cycle and survival of PC12 cells

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  • Johansen, Valdemar Brimnes Ingemann
  • Elizabeth Hampson
  • Elpida Tsonou
  • Chiara Pantarelli
  • Julia Y. Chu
  • Laraine Crossland
  • Hanneke Okkenhaug
  • Andrew J. Massey
  • David C. Hornigold
  • Heidi C.E. Welch
  • Stephen A. Chetwynd
Norbin is an adaptor protein that binds numerous G protein-coupled receptors (GPCRs), is highly expressed in neurons, and is essential for a functioning nervous system in rodent models. Yet, beyond its control of neurite outgrowth and synaptic plasticity, few cellular roles of Norbin have been investigated to date. Furthermore, while Norbin is known to regulate the steady-state cell surface levels of several GPCRs, only in one case has the protein been shown to control the agonist-induced receptor internalisation which serves to attenuate GPCR signalling. Here, we generated a Norbin-deficient PC12 cell line which enabled us to study both the cellular functions of Norbin and its roles in GPCR trafficking and signalling. We show that Norbin limits cell size and spreading, and is required for the growth, viability and cell cycle progression of PC12 cells. We also found that Norbin regulates both the steady-state surface level and agonist-induced internalisation of the GPCR sphingosine-1-phosphate receptor 1 (S1PR1) in these cells, suggesting that its role in agonist-dependent GPCR trafficking is more widespread than previously appreciated. Finally, we show that Norbin limits the S1P-stimulated activation of Akt and p38 Mapk, and is required for the activation of Erk in PC12 cells. Together, our findings provide a better understanding of the cellular functions of Norbin and its control of GPCR trafficking.
OriginalsprogEngelsk
Artikelnummer18237
TidsskriftScientific Reports
Vol/bind13
Udgave nummer1
Antal sider13
ISSN2045-2322
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We gratefully acknowledge the support of Professor Rod Hubbard from the University of York and Vernalis in the initiation and oversight of this project. We thank Dr Simon Andrews, Head of the Babraham Bioinformatics facility, and the staff of the Babraham Imaging and Flow Cytometry facilities for their dedicated and highly skilled support. This research was funded by Institute Strategic Programme Grant BB/P013384/1 from the BBSRC to the Signalling Programme at the Babraham Institute. V. B. I. J. was supported by a Peter and Emma Thomsen Scholarship. E.H. received an iCASE studentship from the BBSRC in collaboration with Vernalis (R&D) Ltd. E.T. received an iCASE studentship from the BBSRC in collaboration with AstraZeneca-MedImmune. S.A.C. is the recipient of a targeted PhD studentship from the MRC.

Funding Information:
We gratefully acknowledge the support of Professor Rod Hubbard from the University of York and Vernalis in the initiation and oversight of this project. We thank Dr Simon Andrews, Head of the Babraham Bioinformatics facility, and the staff of the Babraham Imaging and Flow Cytometry facilities for their dedicated and highly skilled support. This research was funded by Institute Strategic Programme Grant BB/P013384/1 from the BBSRC to the Signalling Programme at the Babraham Institute. V. B. I. J. was supported by a Peter and Emma Thomsen Scholarship. E.H. received an iCASE studentship from the BBSRC in collaboration with Vernalis (R&D) Ltd. E.T. received an iCASE studentship from the BBSRC in collaboration with AstraZeneca-MedImmune. S.A.C. is the recipient of a targeted PhD studentship from the MRC.

Publisher Copyright:
© 2023, Springer Nature Limited.

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