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Mol. Cells 2010; 29(5): 443-448

Published online May 31, 2010

https://doi.org/10.1007/s10059-010-0080-5

© The Korean Society for Molecular and Cellular Biology

Asymmetric Tyrosine Kinase Arrangements in Activation or Autophosphorylation of Receptor Tyrosine Kinases

Jae Hyun Bae*, and Joseph Schlessinger

Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8066, USA

Correspondence to : *Correspondence: jaehyunbae@hotmail.com

Received: April 19, 2010; Accepted: April 22, 2010

Abstract

Receptor tyrosine kinases (RTKs) play important roles in the control of many cellular processes including cell proliferation, cell adhesion, angiogenesis, and apoptosis. Ligand-induced dimerization of RTKs leads to autophosphorylation and activation of RTKs. Structural studies have shown that while isolated ectodomains of several RTKs form symmetric dimers the isolated cytoplasmic kinase domains of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) form asymmetric dimers during their activation. Binding of one kinase molecule of EGFR to a second kinase molecule asymmetrically leads to stimulation of kinase activity and enhanced autophosphorylation. Furthermore, the structures of the kinase domain of FGFR1 and FGFR2 reveal the formation of asymmetric interfaces in the processes of autophosphorylation at their specific phosphotyrosine (pY) sites. Disruption of asymmetric dimer interface of EGFR leads to reduction in enzymatic activity and drastic reduction of autophosphorylation of FGFRs in ligand-stimulated live cells. These studies demonstrate that asymmetric dimer formation is as a common phenomenon critical for activation and autophosphorylation of RTKs.

Keywords , cell signaling, phosphorylation, protein kinase, x-ray crystallography

Article

Minireview

Mol. Cells 2010; 29(5): 443-448

Published online May 31, 2010 https://doi.org/10.1007/s10059-010-0080-5

Copyright © The Korean Society for Molecular and Cellular Biology.

Asymmetric Tyrosine Kinase Arrangements in Activation or Autophosphorylation of Receptor Tyrosine Kinases

Jae Hyun Bae*, and Joseph Schlessinger

Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8066, USA

Correspondence to:*Correspondence: jaehyunbae@hotmail.com

Received: April 19, 2010; Accepted: April 22, 2010

Abstract

Receptor tyrosine kinases (RTKs) play important roles in the control of many cellular processes including cell proliferation, cell adhesion, angiogenesis, and apoptosis. Ligand-induced dimerization of RTKs leads to autophosphorylation and activation of RTKs. Structural studies have shown that while isolated ectodomains of several RTKs form symmetric dimers the isolated cytoplasmic kinase domains of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) form asymmetric dimers during their activation. Binding of one kinase molecule of EGFR to a second kinase molecule asymmetrically leads to stimulation of kinase activity and enhanced autophosphorylation. Furthermore, the structures of the kinase domain of FGFR1 and FGFR2 reveal the formation of asymmetric interfaces in the processes of autophosphorylation at their specific phosphotyrosine (pY) sites. Disruption of asymmetric dimer interface of EGFR leads to reduction in enzymatic activity and drastic reduction of autophosphorylation of FGFRs in ligand-stimulated live cells. These studies demonstrate that asymmetric dimer formation is as a common phenomenon critical for activation and autophosphorylation of RTKs.

Keywords: , cell signaling, phosphorylation, protein kinase, x-ray crystallography

Mol. Cells
Aug 31, 2022 Vol.45 No.8, pp. 513~602
COVER PICTURE
Cryo-EM structure of human porphyrin transporter ABCB6 (main figure) shows that binding of hemin (inset, magenta) in concert with two glutathione molecules (cyan) primes ABCB6 for high ATP turnover (Kim et al., pp. 575-587).

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