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Receptor Tyrosine Kinase Signal Transduction and the Molecular Basis of Signalling Specificity

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Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

Abstract

Present in all multicellular organisms, receptor tyrosine kinases (RTKs) play a major role in regulating critical cellular processes and in their alterations in cancer and metabolic diseases. Since the cloning of the first RTK (the EGF receptor) 30 years ago, considerable progress has been made in the structural biology of both the extracellular domains and the tyrosine kinase domains of many members of the RTK superfamily. These studies have firmly established the general paradigm that ligand-bound RTKs function as dimeric allosteric enzymes and that several exhibit negative cooperativity in binding. Much work remains to be done to understand the exact nature of the allosteric mechanisms that transmit the extracellular conformational changes to the kinase domains. The activation of the kinase domains results in intermolecular transphosphorylation which allows recruitment of substrates that have affinity for phosphorylated tyrosyls through SH2 and PTB domains, resulting in the assembly of a signal transduction particle and in the activation of complex intracellular phosphorylation cascades. While we have learned much about the details of the intracellular signalling networks, their modular structure and their general organisation including negative feedbacks, the molecular mechanisms of signalling specificity by the various growth factors through their distinct receptors remain an enigma given the commonality of the signalling network that links the activated receptors to the biological endpoints including the regulation of the cell cycle and apoptosis. Systems biology approaches are clearly needed for a quantitative understanding of the combinatorial nature of the RTKs signalling networks.

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Acknowledgements

I would like to acknowledge many enlightening discussions on RTKs over many years with Yossi Schlessinger, Yossi Yarden, Axel Ullrich, Ralph Bradshaw, Boris Kholodenko, Steve Wiley, Colin Ward and Mike Lawrence, as well as the many friends and colleagues who participated in the 37th European Symposium on Hormones and Cell Regulation on “RTKs from structural biology to systems biology” that I organised in Mont Sainte-Odile in October 2012.

Note I discovered after completion of this chapter an excellent review by Ichiro N. Maruyama [126] that discusses several issues also discussed in my chapter, and contains many additional references.

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  1. De Meyts R&D Consulting, Avenue Reine Astrid 42, 1950, Kraainem, Belgium

    Pierre De Meyts M.D., Ph.D.

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  1. Pierre De Meyts M.D., Ph.D.
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Correspondence to Pierre De Meyts M.D., Ph.D. .

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  1. Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

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De Meyts, P. (2015). Receptor Tyrosine Kinase Signal Transduction and the Molecular Basis of Signalling Specificity. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2053-2_4

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