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ZFIN ID: ZDB-PUB-110719-40
Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function
Persaud, A., Alberts, P., Hayes, M., Guettler, S., Clarke, I., Sicheri, F., Dirks, P., Ciruna, B., and Rotin, D.
Date: 2011
Source: The EMBO journal   30(16): 3259-73 (Journal)
Registered Authors: Ciruna, Brian, Hayes, Madeline
Keywords: E3 ubiquitin ligase, endocytosis, FGF receptor, Nedd4, WW domain
MeSH Terms:
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Body Patterning/physiology
  • Cell Differentiation/physiology
  • Central Nervous System/embryology
  • Endocytosis/physiology*
  • Endosomal Sorting Complexes Required for Transport/genetics
  • Endosomal Sorting Complexes Required for Transport/physiology*
  • Gene Knockdown Techniques
  • Humans
  • Molecular Sequence Data
  • Neurons/cytology
  • Peptide Fragments/metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational*
  • Protein Transport
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 1/chemistry
  • Receptor, Fibroblast Growth Factor, Type 1/genetics
  • Receptor, Fibroblast Growth Factor, Type 1/physiology*
  • Recombinant Fusion Proteins/physiology
  • Signal Transduction/physiology
  • Species Specificity
  • Stem Cells/cytology
  • Substrate Specificity
  • Ubiquitin-Protein Ligases/genetics
  • Ubiquitin-Protein Ligases/physiology*
  • Ubiquitination
  • Zebrafish/embryology
PubMed: 21765395 Full text @ EMBO J.
ABSTRACT
Fibroblast growth factor receptor 1 (FGFR1) has critical roles in cellular proliferation and differentiation during animal development and adult homeostasis. Here, we show that human Nedd4 (Nedd4‐1), an E3 ubiquitin ligase comprised of a C2 domain, 4 WW domains, and a Hect domain, regulates endocytosis and signalling of FGFR1. Nedd4‐1 binds directly to and ubiquitylates activated FGFR1, by interacting primarily via its WW3 domain with a novel non‐canonical sequence (non‐PY motif) on FGFR1. Deletion of this recognition motif (FGFR1‐Δ6) abolishes Nedd4‐1 binding and receptor ubiquitylation, and impairs endocytosis of activated receptor, as also observed upon Nedd4‐1 knockdown. Accordingly, FGFR1‐Δ6, or Nedd4‐1 knockdown, exhibits sustained FGF‐dependent receptor Tyr phosphorylation and downstream signalling (activation of FRS2α, Akt, Erk1/2, and PLCγ). Expression of FGFR1‐Δ6 in human embryonic neural stem cells strongly promotes FGF2‐dependent neuronal differentiation. Furthermore, expression of this FGFR1‐Δ6 mutant in zebrafish embryos disrupts anterior neuronal patterning (head development), consistent with excessive FGFR1 signalling. These results identify Nedd4‐1 as a key regulator of FGFR1 endocytosis and signalling during neuronal differentiation and embryonic development.
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