Invited ReviewThe ErbB/HER family of protein-tyrosine kinases and cancer
Graphical abstract
Introduction
The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, are among the most studied cell signaling families in biology [1]. Cohen initiated this line of investigation and described epidermal growth factor (EGF), its receptor (EGFR), and its biochemical actions [2]. He discovered that the EGF receptor was a protein-tyrosine kinase, which was a revolutionary finding at the time (see Ref. [3] for a historical review). Cohen et al. found that a solubilized 170 kDa polypeptide contains both EGF binding activity and protein kinase activity [4]. EGFR was also the first receptor that provided evidence for a relationship between receptor overexpression and cancer [5]. EGFR is among the most studied receptor protein-tyrosine kinases owing to its general role in signal transduction and in oncogenesis.
The human protein kinase family consists of more than 500 members thereby making it one of the largest gene families [6]. These enzymes catalyze the following reaction:MgATP−1 + proteinOH → ProteinOPO32− + MgADP + H+
Based upon the nature of the phosphorylated OH group, these proteins are classified as protein-serine/threonine kinases (385 members), protein-tyrosine kinases (90 members), and tyrosine-kinase like proteins (43 members). Moreover, there are 106 protein kinase pseudogenes. Of the 90 protein-tyrosine kinases, 58 are receptor and 32 are non-receptor kinases. A small group of dual-specificity kinases including MEK1 and MEK2 catalyze the phosphorylation of both tyrosine and threonine in target proteins; dual-specificity kinases possess molecular features that place them within the protein-serine/threonine kinase family. Protein phosphorylation is the most widespread class of post-translational modification used in signal transduction. Families of protein phosphatases catalyze the dephosphorylation of proteins thus making phosphorylation–dephosphorylation an overall reversible process [7].
Protein kinases play a predominant regulatory role in nearly every aspect of cell biology [6]. They regulate apoptosis, cell cycle progression, cytoskeletal rearrangement, differentiation, development, the immune response, nervous system function, and transcription. Moreover, dysregulation of protein kinases occurs in a variety of diseases including cancer, diabetes, and autoimmune, cardiovascular, inflammatory, and nervous disorders. Considerable effort has been expended to determine the physiological and pathological functions of receptor protein-kinase signal transduction pathways during the past 30 years.
Section snippets
ErbB protein kinases
The human EGF receptor family consists of four members (HER1–4) that belong to the ErbB lineage of proteins (ErbB1–4). This family of receptors is ubiquitously expressed in epithelial, mesenchymal, and neuronal cells and their cellular progenitors. The gene symbol, ERBB, is derived from the name of the avian viral erythroblastosis oncogene to which these receptors are related. Human gene symbols generally are italicized with all letters in uppercase (EGFR). Italics are not necessary in gene
The extracellular ligand-binding domains
Binding of growth factors to ErbB1/3/4 promotes dimerization of monomeric receptors and increases the tyrosyl kinase activity of the intracellular domains of ErbB1/2/4 [32]. Although ErbB2 lacks a soluble ligand or growth factor, it readily forms heterodimers. There are a number of possible ways that a growth factor or ligand can induce receptor dimerization. One possibility for growth-factor induced receptor dimerization involves a single ligand that interacts simultaneously with two receptor
ErbB signaling
The ErbB/HER signaling networks consist of several modules that are interconnected and overlapping [80]. These include the phosphatidylinositol 3-kinase (PI3K)/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. The PI3K/Akt pathway plays an important role in mediating cell survival and the Ras/ERK1/2 and PLCγ pathways participate in cell proliferation [81]. These and other ErbB signaling modules participate in angiogenesis, cell adhesion, cell motility,
Classification and general treatment
Lung cancer is the most prevalent malignancy in the world [140]. In 2008, the estimated global incidence of lung cancer was about 1.6 million with about 1.4 million deaths attributed to this malignancy. In 2012, the estimated incidence of lung cancer in the United States was about 228,000 with about 160,000 deaths [141]. These data indicate that lung cancer is a disease of high mortality and that more effective treatments are needed. Lung cancers are classified clinically into two major groups:
Orally active ErbB protein kinase domain inhibitors, Lipinski's rule of five, lipophilic efficiency, and ligand efficiency
Pharmacologists and medicinal chemists have searched for drug-like chemical properties that result in compounds with oral therapeutic efficacy in a predictable fashion. Lipinski's “rule of five” represents an initial experimental and computational approach to estimate solubility, permeability, and efficacy in the drug discovery and development setting [270]. This rule predicts that poor absorption or permeation is more likely when there are more than 5 hydrogen-bond donors, 10 (5 × 2)
Adverse effects and toxicity of non-targeted and targeted anticancer agents
Although nearly all drugs have associated adverse side-effects and toxicities, these are considerably more serious for cytotoxic drugs than for targeted agents [146]. Cytotoxic agents indiscriminately cause macromolecular lesions whereas targeted therapies regulate the activity of specific signaling pathways. The cytotoxic agents are poisons that wreak havoc on the recipient; moreover, many of them are administered at the maximum tolerated dose. The term pharmaceutical is derived from pharmacon
Conflict of interest
The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.
Acknowledgements
The author thanks Prof. John Kuriyan for providing the protein data bank file for the EGFR asymmetric dimer. He also thanks the library staff of the University of North Carolina at Chapel Hill Health Sciences library for providing bibliographic assistance and Laura M. Roskoski for providing editorial support.
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