Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
The epidermal growth factor receptor (EGFR) family consists of four members: EFGR, human epidermal growth factor receptor-2 (HER2), HER3, and HER4. All members of the EGFR family contain an extracellular ligand-binding region, a membrane spanning region and cytoplasmic region, which possesses tyrosine kinase activity. The binding of a ligand to the receptor leads to the formation of either homo or heterodimers between members of the epidermal growth factor receptor family and activation of tyrosine kinase activity (Yarden, 2001). This leads to the binding of adenosine triphosphate (ATP) and phosphorylation of the cytoplasmic component of the kinase. This phosphorylation event allows adaptor proteins to interact with the receptor and initiate the downstream signaling pathways, Fig. 6.1 (Yarden, 2001). Without ligand, the EGFR receptor is found in a closed conformation with the dimerization interface blocked. Unlike EGFR, HER2 has a different extracellular region and has a fixed conformation which results in permanent exposure of the dimerization domain (Garret, 2003). In addition, HER2 is unique among the receptor family in that it binds none of the potential EGF ligands. As a result, it appears that its primary role in the pathway is to form heterodimers with the other receptors (Graus-Porta, 1997). HER3 also plays a distinct role in the HER family signaling network. Although it is kinase inactive and therefore incapable of initiating downstream signaling pathways on its own, HER3 can dimerize with other receptors, particularly HER2, for potent cellular signaling.
REGULATORY MECHANISMS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
Insulin-dependent autophosphorylation of tyrosine residues on the cytosolic beta chains of the insulin receptor opens up its major catalytic domains thereby enhancing tyrosine protein kinase activity over 10-fold. The beta chains bind to neighboring adaptor proteins and phosphor) late tyrosine residues. Two important adaptor proteins of this type, 1RS and She, stand at the head of two major insulin-responsive signal transduction pathways. In figure 3.8 the pathway on the left is labeled PI-3-K (phosphatidyl inositol-J-kinase) for a key intermediate step. The pathway on the right is designated МАРК (mitogen activating protein kinase). Depending on the cell type there are points of cross communication ("cross talk") between the two pathways. The present state of research indicates that the МАРК pathway of liver and adipose tivsue terminates in the nucleus with the induction or repression (transcription) of a set of genes of key enzymes involved in insulin glucagon-sensitive (long term) control of metabolic pathways. The 1'1-3-K pathway signals a general increase in protein synthesis through enhancement of translation and also appears to be chiefly responsible for "short-term" net dephosphorylation of key enzymes in liver, adipose and muscle that promote the formation of glycogen and triglyceride (Section 3.8.1 and Chapters 4 and 7).
The immune response to fungal challenge
Mahmoud A. Ghannoum, John R. Perfect in Antifungal Therapy, 2019
Toll-like receptors (TLRs) are type I integral membrane glycoproteins that belong to the Toll/interleukin-1 receptor (TIR) superfamily. The majority of TLRs are expressed on the cellular surface of immune cells (TLR 1, 2, 4–6, 11), while TLR 3, 7/8, and 9 are located in endosomal compartments [11]. TLRs use a conserved TIR domain in the cytosolic region to activate one of four adaptor proteins: the death-domain containing myeloid differentiation factor 88 (MyD88), TIRAP (TIR-adaptor containing adaptor protein, also known as MyD88-adaptor-like protein, MAL), TRIF (TIR-domain-containing adaptor protein inducing IFN-β), and TRAM (TRIF-adaptor molecule). Differential use of these adaptor proteins confers specificity to the TLR signaling pathways [12]. The majority of TLRs utilize MyD88 signal adaptor proteins to activate IRAKs and TRAF6, which ultimately activate NF-κB and mitogen-activated protein (MAP) kinases to synthesize inflammatory cytokines like IL-6 and TNF-α [13]. In contrast, TLR3-mediated signaling utilizes TRIF and IRF3 in producing type I interferons in a MyD88-independent manner [14]. TLR4 activation uniquely leads to both MyD88-dependent, early phase NF-κB transcription of proinflammatory cytokines (IL-1β, TNF-a, and IL-6) and MyD88-independent, late phase NF-κB transcription of IFN-β [13].
FYB methylation in peripheral blood as a potential marker for the early-stage lung cancer: a case-control study in Chinese population
Published in Biomarkers, 2022
Mengxia Li, Rong Qiao, Runbo Zhong, Yujie Wei, Jun Wang, Zheng Zhang, Ling Wang, Tian Xu, Yue Wang, Liping Dai, Wanjian Gu, Baohui Han, Rongxi Yang
Adaptor proteins play essential roles in various processes including promotion of receptor-mediated signalling, amplification of cellular signals, and changes in the cytoskeleton (Flynn 2001). FYB is the first identified molecular adaptor that linked the signalling of T cell receptor to the integrin activation, inside-out signalling and T cell adhesion (Geng et al. 2001). Changes in integrin signalling pathways such as SLP-76-FYB-SKAP-55 could cause cancers (Zhang and Wang 2012). FYB also participates in the cytoskeletal rearrangement, which has a pivotal role in regulating immune cell function, especially T cell effector functions (Maccari et al. 2016, Schoppmeyer et al. 2017). In addition, FYB was involved in the activation of NF-kappaB, a nuclear factor in the process of oncogenesis (Medeiros et al. 2007, Rasmi et al. 2020). Several studies have suggested the overexpression of FYB in human cancer tissues (Andreopoulos and Anastassiou 2012, Song et al. 2020).
Experimental drugs for the inhibition of preterm labor
Published in Expert Opinion on Investigational Drugs, 2020
Tegan Triggs, Sailesh Kumar, Murray Mitchell
PAMPs initiate the inflammatory cascade when they are recognized by transmembrane pattern recognition receptor (PRRs), such as Toll-like receptors (TLRs). TLRs are expressed on the surface and in various intracellular compartments of cells involved in innate immunity (macrophages and neutrophils). They serve to recruit adaptor proteins which mediate intracellular signaling. TLR4 is a specific receptor on immune cell surfaces, which recognizes LPS molecule. Activation of TLR4 leads to intracellular activation of transforming growth factor beta-activated kinase 1 (TAK1). TAK1 is known to activate two pathways: one which culminates in activation of the NF-κB complex (nuclear factor kappa-light-chain-enhancer of activated B cells), and another which results in activation of mitogen-activated protein kinases (MAPKs).
Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence
Published in Expert Review of Anticancer Therapy, 2021
Matteo Santoni, Roberto Iacovelli, Valentina Colonna, Stephan Klinz, Giorgio Mauri, Marianna Nuti
The complexity of RTK signaling provides multiple potential points of dysregulation. Several intracellular signaling pathways may be activated by a single RTK receptor type. For example, stimulation of the RTK receptor MET (HGF receptor) by its ligand HGF initiates intracellular signaling via several pathways, including phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, RAS/mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, to control processes such as embryogenesis and wound healing [9]. In solid tumors, abnormal MET signaling can increase the activation of these pathways, leading to increased cell invasion, metastasis, tumor proliferation, and angiogenesis [9]. Conversely, some intracellular signaling pathways can be activated by different RTKs that engage with overlapping sets of adaptor proteins. For example, complex crosstalk between the VEGF/VEGFR and HGF/MET signaling pathways has been identified in cell cultures of vascular endothelium [10]. Activation of intracellular kinases by both VEGF and HGF may be synergistic in terms of the effects on enhanced proliferation, chemotaxis, and survival of endothelial cells, resulting in a more robust tumor vasculature than that generated by activation of either pathway alone [10,11].
Related Knowledge Centers
- Growth Factor
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