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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Both normal and mutated Ras proteins need to anchor to the cell membrane for signal transduction to occur (Figure 6.54). Attachment to the membrane occurs through several post-translational modifications, in particular the transfer of a 15-carbon isoprenoid group to the carboxy-terminal of the Ras protein, a process known as prenylation. This isoprenoid group ensures that Ras can attach to its correct intracellular membrane-bound location. Thus, the membrane-bound Ras protein represents a “molecular switch” that allows transport of a signal (e.g., a growth factor) from the external environment of a cell to its nucleus. The first stage of this process involves an extracellular ligand stimulating a monomeric receptor kinase (RTK) that then dimerizes. Next, Grb2, an initial adaptor protein, identifies and interacts with a binding site, which in turn allows recruitment of “Son of Sevenless” (SoS), a second adaptor protein. The latter causes the inactive GDP-carrying Ras to become active by substituting GDP for GTP. After this, the signal can be transmitted downstream by the activated Ras to other effectors, such as Raf. In the MAPK signaling pathway, the Raf protein is the first kinase in the signaling chain.
Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Penelope Bradbury, John Hilton, Janet E. Dancey
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.
Functional Study of Lysosomal Nutrient Transporters
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Xavier Leray, Corinne Sagné, Bruno Gasnier
As adaptor proteins recognize their cargo in the cytosol, the number of motif candidates can be reduced by focusing on cytosolic domains of the transporter. These domains can be inferred from a homologous 3D structure or by predicting the membrane topology with sequence algorithms (for instance, TMHMM or TMpred). Another criterion to select mutations is the evolutionary conservation of putative motifs. However, this criterion should be used with caution as sorting signals may be species-specific even within mammals. Some lysosomal proteins have multiple, functionally redundant sorting signals. Therefore, candidate mutations should be combined if individual mutations fail to disrupt lysosomal localization.
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).
An updated review on exosomes: biosynthesis to clinical applications
Published in Journal of Drug Targeting, 2021
Sheela Modani, Devendrasingh Tomar, Suma Tangirala, Anitha Sriram, Neelesh Kumar Mehra, Rahul Kumar, Dharmendra Kumar Khatri, Pankaj Kumar Singh
In the process of exosomes uptake, exosomes pass the signals to the receiver cell, which involves a three-step mechanism [53]. First, exosomes identify the specific target cell and interact with receptors present on the cell membrane, then exosomes fuse to the membrane of the target cell and followed by the entry of the exosomes in the cell by endocytosis/phagocytosis mechanism. The phagocytosis of exosomes was shown to be dependent on the actin cytoskeleton, phosphatidylinositol 3-kinase (PI3K) and dynamin2. Notably, actin, PI3K and dynamin2 have all been implicated in both clathrin-mediated endocytosis and phagocytosis. Internalised exosomes co-localised with Lamp-1, lysobisphosphatidic acid and Rab7 in late autophagosomes and/or endosomal and lysosomal vesicles [53]. Clathrin-mediated endocytosis utilises clathrin and adaptor protein 2 complexes which coat the membrane and induce the invagination of the membrane into a vesicle [54]. Many reports in the literature also suggested internalisation as the most common mechanism of exosomes uptake, which is mainly dependent upon cell type and proteins present on cell membrane [55]. Uptake of exosomes by a recipient cell is specifically cell-specific, involving the interaction of proteins present on the surface of target cells and exosomes are crucial for recipient cell adhesion and targeting [56].
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).