Receptor tyrosine kinases: biological functions and anticancer targeted therapy

Abstract

Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self‐renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs‐targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.

Phylogenetic and transcriptomic characterization of insulin and growth factor receptor tyrosine kinases in crustaceans

“…Processes such as development, growth, homeostasis, cell proliferation, and metabolism are regulated by growth factors, many of which are mediated by RTKs (3,4,82). In insects, RTK signaling controls molting by stimulating mechanistic target of rapamycin (mTOR)-dependent synthesis and secretion of molting hormones (ecdysteroids) by the prothoracic gland (82,(89)(90)(91)(92)(93).…”

“…In humans, there are 55 RTKs organized into 19 subfamilies or classes, as it is now recognized that three kinases in the lemur class phosphorylate serine/threonine residues ( 1 , 2 ). Of these, five RTK classes are the most common across metazoan taxa: epidermal growth factor receptor (EGFR; Class I); insulin receptor, IGF1 receptor, and the insulin receptor-related receptor (InsR; Class II); platelet-derived growth factor receptor (PDGFR; Class III); vascular endothelial growth factor receptor (VEGFR; Class IV); and fibroblast growth factor receptor (FGFR; Class V) ( 3 , 4 ). All RTKs share a similar organization with an N-terminal extracellular region containing dimerization and ligand-binding domains, an α-helical transmembrane domain, and a C-terminal region containing a tyrosine kinase domain and tyrosine-rich C-terminus.…”

“…InsR ligands include insulin, insulin-like growth factors (IGFs), and insulin-like peptides (ILPs) ( 3 , 7 ). By contrast, EGFRs, FGFRs, PDGFRs, and VEGFRs are monomers in the cell membrane and form homodimers or heterodimers upon binding of their respective ligands and activation ( 3 , 4 , 8 ). Isoforms that differ in ligand binding affinity and specificity are common ( 3 , 7 , 9 – 11 ).…”

“…All RTKs share a similar organization with an N-terminal extracellular region containing dimerization and ligand-binding domains, an a-helical transmembrane domain, and a C-terminal region containing a tyrosine kinase domain and tyrosine-rich C-terminus. An intracellular juxtamembrane segment, located between the transmembrane and tyrosine kinase domains, mediates autoinhibition by interacting with the activation loop in the kinase domain (3)(4)(5)(6). InsR is a heterotetramer of disulfide-linked ab subunits resulting from furin cleavage of a protein precursor (7).…”

“…Isoforms that differ in ligand binding affinity and specificity are common (3,7,(9)(10)(11). Receptor activation results in autophosphorylation of tyrosines in the juxtamembrane segment and the C-terminus and phosphorylation of signal transduction proteins that are recruited to the receptor (3)(4)(5)(6)(7). RTKs can activate various signal transduction pathways, such as MAPK-ERK, PI3K/Akt/mTOR, JAK/STAT, and PLC/PKC, that stimulate cell proliferation, growth, and metabolism (1,3,(5)(6)(7)(9)(10)(11)(12).…”