scholarly journals Epidermal Growth Factor Receptor Phosphorylation Sites Ser991and Tyr998Are Implicated in the Regulation of Receptor Endocytosis and Phosphorylations at Ser1039and Thr1041

2009 ◽  
Vol 8 (9) ◽  
pp. 2131-2144 ◽  
Author(s):  
Jiefei Tong ◽  
Paul Taylor ◽  
Scott M. Peterman ◽  
Amol Prakash ◽  
Michael F. Moran
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Phosphorylation Sites ◽  
Receptor Phosphorylation ◽  
Receptor Endocytosis ◽  
Epidermal Growth

scholarly journals The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis

2008 ◽  
Vol 19 (3) ◽  
pp. 1252-1260 ◽  
Author(s):  
Elsa-Noah N'Diaye ◽  
Aylin C. Hanyaloglu ◽  
Kimberly K. Kajihara ◽  
Manojkumar A. Puthenveedu ◽  
Ping Wu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Negative Regulator ◽  
Regulatory Function ◽  
Receptor Endocytosis ◽  
Epidermal Growth ◽  
G Protein Coupled

The activity of many signaling receptors is regulated by their endocytosis via clathrin-coated pits (CCPs). For G protein-coupled receptors (GPCRs), recruitment of the adaptor protein arrestin to activated receptors is thought to be sufficient to drive GPCR clustering in CCPs and subsequent endocytosis. We have identified an unprecedented role for the ubiquitin-like protein PLIC-2 as a negative regulator of GPCR endocytosis. Protein Linking IAP to Cytoskeleton (PLIC)-2 overexpression delayed ligand-induced endocytosis of two GPCRs: the V2 vasopressin receptor and β-2 adrenergic receptor, without affecting endocytosis of the transferrin or epidermal growth factor receptor. The closely related isoform PLIC-1 did not affect receptor endocytosis. PLIC-2 specifically inhibited GPCR concentration in CCPs, without affecting membrane recruitment of arrestin-3 to activated receptors or its cellular levels. Depletion of cellular PLIC-2 accelerated GPCR endocytosis, confirming its regulatory function at endogenous levels. The ubiquitin-like domain of PLIC-2, a ligand for ubiquitin-interacting motifs (UIMs), was required for endocytic inhibition. Interestingly, the UIM-containing endocytic adaptors epidermal growth factor receptor protein substrate 15 and Epsin exhibited preferential binding to PLIC-2 over PLIC-1. This differential interaction may underlie PLIC-2 specific effect on GPCR endocytosis. Identification of a negative regulator of GPCR clustering reveals a new function of ubiquitin-like proteins and highlights a cellular requirement for exquisite regulation of receptor dynamics.

scholarly journals Growth Factor Receptor Binding Protein 2-mediated Recruitment of the RING Domain of Cbl to the Epidermal Growth Factor Receptor Is Essential and Sufficient to Support Receptor Endocytosis

2005 ◽  
Vol 16 (3) ◽  
pp. 1268-1281 ◽  
Author(s):  
Fangtian Huang ◽  
Alexander Sorkin
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Receptor Binding ◽  
Binding Protein ◽  
Growth Factor Receptor ◽  
Ring Domain ◽  
Receptor Endocytosis ◽  
Epidermal Growth ◽  
Receptor Binding Protein

Knockdown of growth factor receptor binding protein 2 (Grb2) by RNA interference strongly inhibits clathrin-mediated endocytosis of the epidermal growth factor receptor (EGFR). To gain insights into the function of Grb2 in EGFR endocytosis, we have generated cell lines in which endogenous Grb2 was replaced by yellow fluorescent protein (YFP)-tagged Grb2 expressed at the physiological level. In these cells, Grb2-YFP fully reversed the inhibitory effect of Grb2 knockdown on EGFR endocytosis and, moreover, trafficked together with EGFR during endocytosis. Overexpression of Grb2-binding protein c-Cbl did not restore endocytosis in Grb2-depleted cells. However, EGFR endocytosis was rescued in Grb2-depleted cells by chimeric proteins consisting of the Src homology (SH) 2 domain of Grb2 fused to c-Cbl. The “knockdown and rescue” analysis revealed that the expression of Cbl-Grb2/SH2 fusions containing RING finger domain of Cbl restores normal ubiquitylation and internalization of the EGFR in the absence of Grb2, consistent with the important role of the RING domain in EGFR endocytosis. In contrast, the carboxy-terminal domain of Cbl, when attached to Grb2 SH2 domain, had 4 times smaller endocytosis-rescue effect compared with the RING-containing chimeras. Together, the data suggest that the interaction of Cbl carboxy terminus with CIN85 has a minor and a redundant role in EGFR internalization. We concluded that Grb2-mediated recruitment of the functional RING domain of Cbl to the EGFR is essential and sufficient to support receptor endocytosis.

scholarly journals VAV2 regulates epidermal growth factor receptor endocytosis and degradation

Oncogene ◽  
2010 ◽  
Vol 29 (17) ◽  
pp. 2528-2539 ◽  
Author(s):  
S Thalappilly ◽  
P Soubeyran ◽  
J L Iovanna ◽  
N J Dusetti
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Endocytosis ◽  
Epidermal Growth
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