scholarly journals A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation

2010 ◽  
Vol 189 (3) ◽  
pp. 557-571 ◽  
Author(s):  
Yuri Frosi ◽  
Sergio Anastasi ◽  
Costanza Ballarò ◽  
Giulia Varsano ◽  
Loriana Castellani ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egf Receptors ◽  
Genetic Ablation ◽  
Egfr Inhibition ◽  
Catalytic Activation ◽  
Feedback Inhibitor ◽  
Epidermal Growth ◽  
Egfr Kinase

Signaling by epidermal growth factor receptor (EGFR) must be controlled tightly because aberrant EGFR activity may cause cell transformation. Receptor-associated late transducer (RALT) is a feedback inhibitor of EGFR whose genetic ablation in the mouse causes phenotypes due to EGFR-driven excess cell proliferation. RALT inhibits EGFR catalytic activation by docking onto EGFR kinase domain. We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes. Moreover, RALT rescues the endocytic deficit of EGFR mutants unable to undergo either endocytosis (Dc214) or degradation (Y1045F) and mediates endocytosis via a domain distinct from that responsible for EGFR catalytic suppression. Consistent with providing a scaffolding function for endocytic proteins, RALT drives EGFR endocytosis by binding to AP-2 and Intersectins. These data suggest a model in which binding of RALT to EGFR integrates suppression of EGFR kinase with receptor endocytosis and degradation, leading to durable repression of EGFR signaling.

scholarly journals Absence of Mutations in the Epidermal Growth Factor Receptor (EGFR) Kinase Domain in Patients with Mesothelioma

2009 ◽  
Vol 4 (4) ◽  
pp. 559 ◽  
Author(s):  
Vamsidhar Velcheti ◽  
Yumi Kasai ◽  
Avinash K. Viswanathan ◽  
Jon Ritter ◽  
Ramaswamy Govindan
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Epidermal Growth ◽  
Egfr Kinase

scholarly journals A highly efficient peptide substrate for EGFR activates the kinase by inducing aggregation

2013 ◽  
Vol 453 (3) ◽  
pp. 337-344 ◽  
Author(s):  
Kate Engel ◽  
Tomoaki Sasaki ◽  
Qi Wang ◽  
John Kuriyan
Keyword(s):  
Kinase Activity ◽  
Growth Factor Receptor ◽  
Catalytic Efficiency ◽  
Kinase Domain ◽  
Receptor Kinase ◽  
Peptide Substrate ◽  
Peptide Substrates ◽  
Epidermal Growth ◽  
Asymmetric Dimer ◽  
Egfr Kinase

Formation of an asymmetric dimer by the EGFR (epidermal growth factor receptor) kinase domains results in allosteric activation. Since this dimer does not readily form in solution, the EGFR kinase domain phosphorylates most peptide substrates with a relatively low catalytic efficiency. Peptide C is a synthetic peptide substrate of EGFR developed by others that is phosphorylated with a significantly higher catalytic efficiency, and we sought to understand the basis for this. Peptide C was found to increase EGFR kinase activity by promoting formation of the EGFR kinase domain asymmetric dimer. Activation of the kinase domain by Peptide C also enhances phosphorylation of other substrates. Aggregation of the EGFR kinase domain by Peptide C probably underlies activation, and Peptide C precipitates several other proteins. Peptide C was found to form fibrils independent of the presence of EGFR, and these fibrils may facilitate aggregation and activation of the kinase domain. These results establish that a peptide substrate of EGFR may increase catalytic activity by promoting kinase domain dimerization by an aggregation-mediated mechanism.

scholarly journals Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer

2008 ◽  
Vol 26 (10) ◽  
pp. 1742-1751 ◽  
Author(s):  
Amit Kumar ◽  
Edward T. Petri ◽  
Balazs Halmos ◽  
Titus J. Boggon
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Human Cancer ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Atomic Level ◽  
Epidermal Growth ◽  
Egfr Kinase

Purpose To review the recent advances in the atomic-level understanding of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated. Methods The analysis was conducted on published crystal structures deposited in the Protein Data Bank ( www.pdb.org ) using the program O. Results In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared with the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors. Conclusion There are now more crystal structures published for the EGFR-TK domain than for any other TK. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

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