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Negative regulation of signaling by the EGFR family

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EGFR Signaling Networks in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Signaling through the EGFR or ErbB family of receptor tyrosine kinases must be precisely regulated to ensure the fidelity of tissue development and homeostasis, yet prevent tumor initiation and progression. The efficiency of receptor signaling in cells is tempered by a series of negative regulatory mechanisms that act directly on receptors to suppress their response to growth factor ligand. The past ten years have witnessed significant progress in the discovery of these pathways and the characterization of the mechanisms by which their loss in tumors might contribute to malignancy. These mechanisms include pathways that lead to receptor degradation, both in the absence and presence of activating ligand. The central components of such pathways are often E3 ubiquitin ligases, such as cbl or Nrdp1. Other mechanisms suppress the ability of receptors to respond to growth factor stimulation. Splice variants of ErbB receptor extracellular domains, proteins that contain leucine-rich repeats in their extracellular domains, and intracellular suppressor proteins such as RALT fall into this category. Here we review ErbB negative regulatory mechanisms, emphasizing what is known about the loss of these pathways in tumors, and highlighting the notion that pathway augmentation or restoration to tumor cells could ultimately be of therapeutic benefit to cancer patients.

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Acknowledgements

Kermit Carraway is supported by NIH grants GM068994 and CA123541, and Colleen Sweeney is supported by NIH grant CA118384. Lily Yen is the recipient of a DoD Breast Cancer Research Program postdoctoral fellowship.

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  1. UC Davis Cancer Center Research Building III, Room 1400 4645 2nd Avenue, Sacramento, CA, 95817

    Kermit L. Carraway III PhD, Lily Yen, Ellen Ingalla & Colleen Sweeney

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  1. Kermit L. Carraway III PhD
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  2. Lily Yen
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  1. OSI Pharmaceuticals, Inc., Bioscience Park Drive 1, Farmingdale, 11735, U.S.A.

    John D. Haley

  2. Dept. Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, United Kingdom

    William John Gullick

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Carraway, K.L., Yen, L., Ingalla, E., Sweeney, C. (2008). Negative regulation of signaling by the EGFR family. In: Haley, J., Gullick, W. (eds) EGFR Signaling Networks in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-356-1_12

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