Hypophosphorylation of residue Y1045 leads to defective downregulation of EGFRvIII

  title={Hypophosphorylation of residue Y1045 leads to defective downregulation of EGFRvIII},
  author={Wei Han and Tao Zhang and Hong Yu and John Foulke and Careen K. Tang},
  journal={Cancer Biology \& Therapy},
  pages={1361 - 1368}
Down-regulation of the EGF receptor is the net result of receptor degradation and recycling. Cbl functions by specifically targeting activated ErbB receptors for ubiquitination, facilitating ligand-induced desensitization of EGFR. The interaction between EGFR and c-Cbl has been shown to depend upon receptor phosphorylation at tyrosine residue 1045, the major docking site for c-Cbl. To better understand the biological consequences of EGFR mutants in human cancers, we compared wild-type EGFR and… 

EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes.

The results suggest that the long lifetime of EGFRvIII is caused by inefficient internalization and impaired sorting to lysosomes due to lack of effective ubiquitinylation.

Gefitinib-sensitive EGFR lacking residues 746-750 exhibits hypophosphorylation at tyrosine residue 1045, hypoubiquitination, and impaired endocytosis.

Data suggest that the signal transduction pathways initiated from these mutant forms are different, and that impaired endocytosis might be responsible for the prolonged signals mediated by the deletion-mutant EGFR.

Cyclic trans-phosphorylation in a homodimer as the predominant mechanism of EGFRvIII action and regulation

It is proposed that EGFRvIII is predominantly regulated dynamically by phosphatases that counteract the process of trans-phosphorylation occurring within the homodimers.

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

This study examines the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain and finds that EGFR vIII retains interaction withLRIG1 and is in fact more sensitive to LRIG 1 action than wild-type receptor.

Impaired degradation followed by enhanced recycling of epidermal growth factor receptor caused by hypo-phosphorylation of tyrosine 1045 in RBE cells

In RBE cells, up-regulation of EGFR Tyr1045 phosphorylation is a potentially useful molecular alteration in EGFR-targeted therapy and shows promise in future treatments of cholangiocarcinoma.

Tyrosine 1045 codon mutations in exon 27 of EGFR are infrequent in oral squamous cell carcinomas.

The lack of identification of mutation in the tyrosine 1045 codon of EGFR suggests that mutations in this region may be relatively rare in oral squamous cell carcinomas.

Endosomal trafficking of the EGFR mutant, EGFRvIII, results in exosomal secretion that triggers astrocyte reactivity

EGFRvIII-containing exosomes derived from GBM cells induce changes in astrocytes that mimic reactive astrogliosis including an increase in glial fibrillary acidic protein (GFAP).

EGFRvIII: An Oncogene with Ambiguous Role

Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered

In this review, the evidence for the expression of EGFRvIII in a range of tumor types is critically analyzed and recent findings pertinent to its function and biology in GBM are discussed.

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

It is shown that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation, and uncovered a unique tumor suppression mechanism involving the regulation of receptor trafficking.



EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

The EGfrvIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRv III immunotoxins.

The RING Finger of c-Cbl Mediates Desensitization of the Epidermal Growth Factor Receptor*

It is demonstrated that the RING type zinc finger of c-Cbl is essential for ubiquitination and subsequent desensitization of EGFR and plays an essential direct role in ubiquitin ligation.

Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization

It is shown that ΔEGFR did not interact with Cbls, SETA, or endophilin A1, providing a mechanistic explanation for its lack of internalization.

Glycosylation-induced Conformational Modification Positively Regulates Receptor-Receptor Association

The studies revealed that the high Kinase activity of the ΔEGFR is due to self-dimerization, and contrary to earlier reports, the kinase activity per molecule of the dimeric Δ EGFR is comparable to that of the EGF-stimulated wild-type receptor.

Transformational and altered signal transduction by a naturally occurring mutant EGF receptor.

Results indicate that high-level expression of the EGFRvIII induces down-regulation of the ras-MAP kinase pathway and that other components involved in EGF receptor signal transduction may play a greater role in neoplastic transformation by the EGfrvIII.

The Enhanced Tumorigenic Activity of a Mutant Epidermal Growth Factor Receptor Common in Human Cancers Is Mediated by Threshold Levels of Constitutive Tyrosine Phosphorylation and Unattenuated Signaling*

Mutational analysis showed that the enhanced tumorigenicity was dependent on intrinsic tyrosine kinase activity and was mediated through the carboxyl terminus, suggesting that the biological functions of ΔEGFR are due to low constitutive activation with mitogenic effects amplified by failure to attenuate signaling by receptor down-regulation.

A mutant EGF‐receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling

It is reported that defective Tyr1045 of EGFR, an inducible c‐Cbl docking site, enhances the mitogenic response to EGF, and Grb2 can terminate signal transduction by accelerating c-Cbl‐dependent sorting of active tyrosine kinases to destruction.

Constitutive Activation of c-Jun N-terminal Kinase by a Mutant Epidermal Growth Factor Receptor*

Findings implicate constitutive activation of the JNK pathway in transformation by EGFRvIII, a constitutively active, naturally occurring mutation of the EGF receptor that is found in many types of human tumors.

Drug‐induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy

An unexpected activity of TKIs is reported: along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB‐2 molecules.