Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The type I RTK kinase family consists of four distinct but closely related receptors: epidermal growth factor receptor 1 (EGFR, ErbB1, Her1), 2 (HER2, ErbB2), 3 (Her3, ErbB3), and 4 (HER4, ErbB4). In response to the binding of various ligands, these kinases undergo heterodimerization and homodimerization, resulting in the activation of numerous growth factor signaling pathways. Therefore, inhibiting these activated pathways can lead to an antitumor effect. In a large variety of tumor types the over-expression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. For example, in gastric cancer approximately 10% of tumors have amplification of the HER2 gene. Therefore, the HER-family of receptors has been a key target for the development of anticancer therapeutics.
Epidermal Growth Factor Receptor Inhibition in Non–Small Cell Lung Cancer
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
The epidermal growth–factor receptor (EGFR, HER1) is a member of the HER family of membrane receptors (HER1–4). The other members are HER2 (also termed ErbB2 or HER2/neu), HER3 (also termed ErbB3), and HER4 (also termed ErbB4). These receptors share the same molecular structure with an extracellular, cysteine-rich, ligand-binding domain, a single α-helix transmembrane domain, and an intracellular domain with tyrosine–kinase (TK) activity in the carboxy-terminal tail (excepting the HER3) (1). The TK domains of HER2 and HER4 show an 80% homology to that of the EGFR (2). Epidermal growth factor (EGF), transforming growth factor-α (TGF-α), and amphiregulin bind exclusively to the EGFR, whereas betacellulin and epiregulin bind both EGFR and HER4. Ligand binding induces EGFR homodimerization as well as heterodimerization with other types of HER proteins (3,4). HER2 does not bind to any known ligand, but it is the preferred heterodimerization partner for EGFR after ligand-induced activation (5). EGFR/EGFR homodimers are unstable, whereas EGFR/HER2 heterodimers are stable and recycle more rapidly to the cell surface (6).
Genetic Susceptibility to Colorectal Cancer
Jim Cassidy, Patrick Johnston, Eric Van Cutsem in Colorectal Cancer, 2006
The function of the APC gene product is the focus of much research interest and the complexities of the cellular role of APC have yet to be fully understood. The APC protein is expressed in epithelial cells in the upper portions of the colonic crypts, suggesting involvement in colonocyte maturation (100–101). Several functional domains are revealed in the protein sequence including the N-terminal homodimerization sequences, as well as numerous other cellular processes such as cellular adhesion, cell-cycle regulation, apoptosis, differentiation, and intracellular signal transduction. The central region of the protein contains β-catenin binding and regulatory domains as well as binding domains for the axin family of proteins. APC appears to influence cellular adhesion by affecting the interaction between catenins and E-cadherin, thus promoting the shedding and migration of epithelial cells. In conjunction with other proteins, axin, glycogen synthase kinase 3β (GSK), and other GSK binding proteins, APC plays a critical role in intra-cellular communication by modulating the levels of β-catenin-dependent transcription (102). β-catenin is an important transcription factor for oncogenic proteins such as cyclin D1 and c-myc (103). The pivotal role of abnormalities in the wnt signaling pathway in colorectal tumorigenesis is exemplified by the identification of somatic mutations in many of the components, such as APC, β-catenin, and axin, with somatic APC mutations being identified in ~85% of all colorectal tumors (104).
F11R/JAM-A: why do platelets express a molecule which is also present in tight junctions?
Published in Platelets, 2023
Piotr Kamola, Anna Babinska, Tomasz Przygodzki
As mentioned above, F11R/JAM-A molecules are capable of forming homodimers. This homodimerization occurs in cis-configuration when the dimer is formed by the molecules located in the same cell (Figure 2b). The molecules can also interact in the trans-configuration when they are located on the membrane of two adjacent cells20 (Figure 2c). It is not clear whether cis-homodimerization is required for trans-homophilic interactions. Some data suggest that monomeric F11R/JAM-A can also interact with its counterpart on an adjacent cell.20 The sites responsible for cis- and trans-homophilic interactions lay in distinct parts of D1 domain of the molecule.20 Both types of interactions are believed to be associated with the function of the protein which will be described further.
Isoform-specific activities of the regulatory subunits of phosphatidylinositol 3-kinases – potentially novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2018
Yoshihiro Ito, Jonathan R. Hart, Peter K. Vogt
A genetic analysis has revealed details of the p85α-PTEN interaction [34]. Homodimerization of p85α is a prerequisite for PTEN binding. This homodimerization involves the binding of the SH3 domain of one partner to the PR1 domain of the other in trans, and the dimer is further stabilized by interactions between the two BH domains (also referred to as RhoGAP domains). Mutations that disrupt the contacts between these domains interfere with dimerization and with binding to PTEN. Details of the p85α dimer structure have also been revealed in a study using truncations and applying analytic ultracentrifugation, fluorescence fluctuation spectroscopy, and small-angle X-ray scattering [12]. Important results from this work are the identification of a new binding contact of the p85α dimer in the cSH2 domain and the conclusion that the structure of the p85α dimer is highly flexible, allowing the existence of multiple conformational states. These can be expected to show distinct affinities for the interaction with different protein partners. The critical contacts that bind the p85α dimer to the phosphatase domain of PTEN are located in the PR2 and BH domains. Mutations in BH or PR2 interfere with binding to PTEN, although they do not affect the ability to dimerize [34].
Rationale for IL-37 as a novel therapeutic agent in inflammation
Published in Expert Review of Clinical Immunology, 2022
Claudia A. Nold-Petry, Marcel F. Nold
As a powerful roadblock of inflammatory responses, IL-37 function must be tightly regulated to avoid excessive suppression of innate and adaptive immunity. For example, in mice transgenic for IL-37 (IL-37tg), only little IL-37 protein is detectable under steady-state conditions despite the transgene’s constitutively active CMV promoter; abundance only increases upon inflammatory challenge [1,5,8]. In addition to an mRNA instability element, such regulation is achieved by homodimerization. Cytokine multimerization is common, but in most cases enables signaling. In contrast, the bioactivity of the head-to-head homodimer that is readily assembled by IL-37 molecules even at low concentrations is substantially lower than that of IL-37 monomers [3,11]. This rare structure–function relationship can be exploited by mutating tyrosine in position 85 to alanine, thus preventing dimerization and generating recIL-37 with considerably enhanced bioactivity [3]. To further improve drug-like properties, this IL-37 variant can be fused with an Fc-protein [12].
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