ErbB receptor negative regulatory mechanisms: implications in cancer.
Activation of ErbB receptor tyrosine kinases (RTKs) must be precisely regulated to ensure the fidelity of developmental and homeostatic processes mediated by growth factors. Insufficient receptor stimulation will lead to defects in tissue development, while excessive stimulation can lead to hyperplastic events associated with cancer and other diseases. A coordinated balance of the intensity and timing of receptor signaling, achieved through both receptor activation and negative regulatory mechanisms, is required for signaling fidelity. While considerable effort has gone into understanding mechanisms by which ErbB receptors are activated, our understanding of the suppression of growth factor receptor activity remains limited. While ligand-stimulated receptor degradation is the most thoroughly examined mechanism for preventing hyper-signaling by ErbBs, recent studies indicate that several other mechanisms act directly on receptors to suppress receptor levels, or the magnitude or duration of receptor signaling. ErbB receptor overexpression or aberrant activation contributes to the progression of numerous solid tumor types. Hence, tumor cells must overcome these endogenous receptor negative regulatory mechanisms before they can exploit ErbB receptors to achieve uncontrolled growth. Here we will discuss several proteins that directly interact with ErbB receptors to suppress signaling, highlighting the potential impact of their loss on tumor progression.
Sweeney
Colleen
C
UC Davis Cancer Center, Research Bldg. III, rm 1400, 4645 2nd Avenue, Sacramento, CA 95817, USA. casweeney@ucdavis.edu
Miller
Jamie K
JK
Shattuck
David L
DL
Carraway
Kermit L
KL
D000818:Animals; D018450:Disease Progression; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases