| First Author | Persaud A | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 16 | Pages | 3259-73 |
| PubMed ID | 21765395 | Mgi Jnum | J:382508 |
| Mgi Id | MGI:8314568 | Doi | 10.1038/emboj.2011.234 |
| Citation | Persaud A, et al. (2011) Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J 30(16):3259-73 |
| abstractText | 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-Delta6) abolishes Nedd4-1 binding and receptor ubiquitylation, and impairs endocytosis of activated receptor, as also observed upon Nedd4-1 knockdown. Accordingly, FGFR1-Delta6, or Nedd4-1 knockdown, exhibits sustained FGF-dependent receptor Tyr phosphorylation and downstream signalling (activation of FRS2alpha, Akt, Erk1/2, and PLCgamma). Expression of FGFR1-Delta6 in human embryonic neural stem cells strongly promotes FGF2-dependent neuronal differentiation. Furthermore, expression of this FGFR1-Delta6 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. |
