The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation

2016 ◽  
Vol 479 (2) ◽  
pp. 152-158 ◽  
Author(s):  
Chaeuk Chung ◽  
Geon Yoo ◽  
Tackhoon Kim ◽  
Dahye Lee ◽  
Choong-Sik Lee ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals ZNRF1 Mediates Epidermal Growth Factor Receptor Ubiquitination to Control Receptor Lysosomal Trafficking and Degradation

2021 ◽  
Vol 9 ◽  
Author(s):  
Chia-Hsing Shen ◽  
Chih-Chang Chou ◽  
Ting-Yu Lai ◽  
Jer-En Hsu ◽  
You-Sheng Lin ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Growth Factor Receptor ◽  
Endosomal Trafficking ◽  
Egfr Signaling ◽  
Lysosomal Trafficking ◽  
Epidermal Growth

Activation of the epidermal growth factor receptor (EGFR) is crucial for development, tissue homeostasis, and immunity. Dysregulation of EGFR signaling is associated with numerous diseases. EGFR ubiquitination and endosomal trafficking are key events that regulate the termination of EGFR signaling, but their underlying mechanisms remain obscure. Here, we reveal that ZNRF1, an E3 ubiquitin ligase, controls ligand-induced EGFR signaling via mediating receptor ubiquitination. Deletion of ZNRF1 inhibits endosome-to-lysosome sorting of EGFR, resulting in delayed receptor degradation and prolonged downstream signaling. We further demonstrate that ZNRF1 and Casitas B-lineage lymphoma (CBL), another E3 ubiquitin ligase responsible for EGFR ubiquitination, mediate ubiquitination at distinct lysine residues on EGFR. Furthermore, loss of ZNRF1 results in increased susceptibility to herpes simplex virus 1 (HSV-1) infection due to enhanced EGFR-dependent viral entry. Our findings identify ZNRF1 as a novel regulator of EGFR signaling, which together with CBL controls ligand-induced EGFR ubiquitination and lysosomal trafficking.

scholarly journals HECT E3 Ubiquitin Ligase Nedd4-1 Ubiquitinates ACK and Regulates Epidermal Growth Factor (EGF)-Induced Degradation of EGF Receptor and ACK

2010 ◽  
Vol 30 (6) ◽  
pp. 1541-1554 ◽  
Author(s):  
Qiong Lin ◽  
Jian Wang ◽  
Chandra Childress ◽  
Marius Sudol ◽  
David J. Carey ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ubiquitin Ligase ◽  
Egf Receptor ◽  
E3 Ubiquitin Ligase ◽  
Growth Factor Receptor ◽  
Binding Motif ◽  
Sam Domain ◽  
Uba Domain ◽  
Epidermal Growth

ABSTRACT ACK (activated Cdc42-associated tyrosine kinase) (also Tnk2) is an ubiquitin-binding protein and plays an important role in ligand-induced and ubiquitination-mediated degradation of epidermal growth factor receptor (EGFR). Here we report that ACK is ubiquitinated by HECT E3 ubiquitin ligase Nedd4-1 and degraded along with EGFR in response to EGF stimulation. ACK interacts with Nedd4-1 through a conserved PPXY WW-binding motif. The WW3 domain in Nedd4-1 is critical for binding to ACK. Although ACK binds to both Nedd4-1 and Nedd4-2 (also Nedd4L), Nedd4-1 is the E3 ubiquitin ligase for ubiquitination of ACK in cells. Interestingly, deletion of the sterile alpha motif (SAM) domain at the N terminus dramatically reduced the ubiquitination of ACK by Nedd4-1, while deletion of the Uba domain dramatically enhanced the ubiquitination. Use of proteasomal and lysosomal inhibitors demonstrated that EGF-induced ACK degradation is processed by lysosomes, not proteasomes. RNA interference (RNAi) knockdown of Nedd4-1, not Nedd4-2, inhibited degradation of both EGFR and ACK, and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF-induced degradation of EGFR. Our findings suggest an essential role of Nedd4-1 in regulation of EGFR degradation through interaction with and ubiquitination of ACK.

scholarly journals Role of the ubiquitin ligase ITCH in clathrin-mediated endocytosis of the epidermal growth factor receptor

2021 ◽  
Author(s):  
Riham Ayoubi ◽  
Peter S. McPherson ◽  
Annie Angers
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Ubiquitin Ligase ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Coated Pits ◽  
Epidermal Growth ◽  
First Time

AbstractOnce activated by ligand, epidermal growth factor receptor (EGFR) is endocytosed in clathrin-coated pits. ITCH is an E3 ubiquitin ligase that interacts with and ubiquitinates several proteins involved in clathrin-mediated endocytosis (CME) including endophilin. To further investigate the function of ITCH in EGFR endocytosis, the internalization of fluorescent EGF was measured in ITCH-/- HeLa cells. In the absence of ITCH, there was a significant decrease in the CME of EGF. Rescue experiments using wild-type ITCH confirmed the importance of the protein for normal EGF uptake. ITCH point mutations that disrupt the interaction of ITCH with endophilin failed to rescue the defects in EGFR uptake, as did a non-catalytic form of ITCH. ITCH-/- cells also displayed a delay in the rate of phospho-EGFR degradation as well as prolonged ERK1/2 signaling. Our study uncovers a pathway regulating EGFR trafficking and reveals for the first time that the protein ITCH is required for CME of EGFR.

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