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Receptor Tyrosine Kinases Require a Signal in Addition to Dimerization to Trigger Pathway Activation

44 Pages Posted: 9 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Monica Gonzalez-Magaldi

Monica Gonzalez-Magaldi

University of Texas at Austin - Department of Molecular Biosciences

Jacqueline M. McCabe

Johns Hopkins University - Department of Biophysics and Biophysical Chemistry

Haley N. Cartwright

University of Texas at Austin - Department of Molecular Biosciences

Ningze Sun

University of Texas at Austin - Department of Molecular Biosciences

Daniel J. Leahy

University of Texas at Austin - Department of Molecular Biosciences

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Abstract

Receptor Tyrosine Kinases (RTKs) comprise a diverse group of cell-surface receptors that mediate key signaling events during animal development and are frequently activated in cancer. Ligand-induced dimerization is the canonical mechanism by which RTKs are thought to be activated, but we show here that substitution of the extracellular regions of 10 RTKs representing 7 RTK classes with the dimeric immunoglobulin Fc region results in constitutive receptor phosphorylation but fails to result in phosphorylation of downstream signaling effectors Erk or Akt. Conversely, substitution of RTK extracellular regions with the extracellular region of the Epidermal Growth Factor Receptor results in robust Erk and/or Akt phosphorylation in response to Epidermal Growth Factor. These results indicate that ligand-bound RTK extracellular regions provide a signal in addition to dimerization that is necessary to couple receptor phosphorylation to activation of downstream effectors and that this signal is a shared feature of at least 7 different RTK classes.

Keywords: Receptor Tyrosine Kinase, EGFR, signaling, ERK, AKT, multimerization, dimerization

Suggested Citation

Gonzalez-Magaldi, Monica and McCabe, Jacqueline M. and Cartwright, Haley N. and Sun, Ningze and Leahy, Daniel J., Receptor Tyrosine Kinases Require a Signal in Addition to Dimerization to Trigger Pathway Activation. Available at SSRN: https://ssrn.com/abstract=3516041 or http://dx.doi.org/10.2139/ssrn.3516041
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Monica Gonzalez-Magaldi

University of Texas at Austin - Department of Molecular Biosciences

100 East 24th St.
Austin, TX 78712
United States

Jacqueline M. McCabe

Johns Hopkins University - Department of Biophysics and Biophysical Chemistry

720 Rutland Avenue
Baltimore, MD 21205-2196
United States

Haley N. Cartwright

University of Texas at Austin - Department of Molecular Biosciences

100 East 24th St.
Austin, TX 78712
United States

Ningze Sun

University of Texas at Austin - Department of Molecular Biosciences

100 East 24th St.
Austin, TX 78712
United States

Daniel J. Leahy (Contact Author)

University of Texas at Austin - Department of Molecular Biosciences ( email )

100 East 24th St.
Austin, TX 78712
United States

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