Regulation of Receptor Tyrosine Kinase Signaling and Its Implication in Cancer

Dear Colleagues,

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs regulate key events in cell growth, differentiation, survival, and migration. Aberrant signaling from RTKs has been implicated in many cancers and other diseases. RTKs have been major targets for developing targeted treatments for various cancers.

Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. These RTKs are classified into twenty different families, including the epidermal growth factor receptor (EGFR) family, platelet-derived growth factor receptors (PDGF-R), fibroblast growth factor receptor (FGFR) family, vascular endothelial growth factor receptor (VEGFR) family, insulin receptor (IR) family, RET receptor family, Eph receptor family, and others. Among these RTKs, the EGFR is historically the prototypical RTK. It was the first of this large family of transmembrane receptors to be cloned, and the first for which a clear connection between aberrant receptor function and cancer could be drawn.

The receptors are generally activated via dimerization and substrate presentation. Through diverse means, extracellular ligand binding will typically cause or stabilize receptor dimerization. The dimerization of the receptors allows the trans-phosphorylation of each monomer by its partner receptor, propagating a signal through the plasma membrane.  The activated RTKs bind to many signaling proteins and stimulate the activation of many signaling pathways, including the Ras-Raf-Mek-ERK, PI3K-Akt-Tor, PLC-γ1, STAT, and Src pathways. The specificity and potency of intracellular signaling pathways are determined by positive and negative regulators, the specific composition of activating ligand(s), receptor dimer components, and the diverse range of proteins associated with the tyrosine phosphorylated C-terminal domain of the RTKs. Through the control of these diverse signaling networks, RTKs regulate many critical cellular processes, such as cell proliferation, cell differentiation, cell survival, cell metabolism, cell migration, and the cell cycle.

RTKs are of great clinical interest due to their role in many diseases, notably cancers. Since their discovery, several mechanisms of RTK dysregulation have been identified. RTKs have represented a major class for targeted therapeutics over the past two decades. The focus of novel drug development has shifted towards the identification and targeting of molecular drivers of cancer, including both the receptors themselves, as well as key cellular factors that play important roles in the RTK signaling cascade. There are two main approaches for targeted therapy: antibodies and small molecules. 

In spite of significant advances in our understanding of RTK signaling, some critical knowledge is still lacking. Novel signaling pathways and cell functions are continuously identified as being regulated by various RTK families. Although more and more novel targeted therapeutics have been developed against RTKs and their signaling pathways, many of these targeted therapeutics eventually result in the rapid development of acquired resistance and subsequent tumor relapse. Overcoming the drug resistant becomes an urgent issue. This Special Issue will cover the recent progress in all areas related to RTK signaling and cancer.

Prof. Dr. Zhixiang Wang
Guest Editor

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