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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Activation of the EGFR pathway is initiated when an appropriate ligand (e.g., TGF-α or EGF in the case of EGFR) binds to the inactive single units of the receptor (Figure 6.22). This causes the receptors to pair together to form a dimer that may be formed either from two identical receptors (e.g., two EGFR-1 receptors pairing to form a homodimer) or from non-identical receptors (e.g., EGFR and HER2/neu receptors pairing to give an asymmetrical heterodimer). This pairing process activates the tyrosine kinase enzyme located in the intracellular domain, which then leads to transphosphorylation of both intracellular domains. This, in turn, initiates a cascade of phosphorylation events involving proteins such as the RAS, RAF, and MEK kinases that eventually results in a signal arriving at the nucleus. This stimulates the expression of genes leading to behaviors such as cell growth, proliferation, survival, migration, and transformation.
Oxidative stress and pre-eclampsia
Published in Pankaj Desai, Pre-eclampsia, 2020
Though there are many known types of VEGF, the activity of VEGF-A was identified first. Before other types of VEGF were discovered, VEGF-A was only known and therefore was named simply VEGF. However later on other types of VEGF got identified and were classified as VEGF-A, B, and so on. All types of VEGF family members act by binding on cell surfaces to receptors. In cases of VEGF, there are tyrosine kinase receptors (VEGFRs) on the cell surface. VEGF bind to VEGFRs to dimerize them. This leads to activation through the process of transphosphorylation. In pregnancy, there has been a high and positive correlation between VEGF and hormones, reflecting placental function like human chorionic gonadotropin (HCG) and progesterone. VEGF production may be increased by these two placental hormones, having a positive effect on trophoblast development. The functions of different VEGF are summarized in Table 4.1.
The Twentieth Century
Published in Arturo Castiglioni, A History of Medicine, 2019
The storage of potential energy is one other factor to be mentioned in the “storage-battery concept” of the supply of energy. Since the time of Harden and Young (1904), phosphates have assumed a dominant importance in energy exchange. “Transphosphorylation” has been established as an important mechanism, the main participators being phosphocreatine (C. H. fiske and Y. subaroff, 1927; P. and G. P. eggleton, 1927) and adenosine di- and tri-phosphate (K. Lohmann and O. Meyerhof, 1934) and possibly an enzyme in the muscle protein, myosin (W. A. englehardt, 1940-2). The concept of the storage of energy in the organism owes much to the brilliant demonstration (1941) by Fritz lipmann of the role of the high-energy phosphate bond in the above compounds and in acetyl phosphate and the pyruvic- and glyceric-acid phosphates.
Dysregulated metabolism: A friend-to-foe skewer of macrophages
Published in International Reviews of Immunology, 2023
Keywan Mortezaee, Jamal Majidpoor
PKM2 induction can be a response to the macrophage activation by LPS. Outcomes of a study showed a negative relation between PKM2 tetramerization with Warburg effect and LPS-induced M1 polarization of bone marrow-derived macrophages. Palsson-McDermott and colleagues in this study showed an inverse relation between PKM2 activators with succinate accumulation and glycolysis in LPS-induced macrophages [51]. However, there are reports on the other side in which cytosolic PKM2 acts as a glycolytic enzyme for catalyzing transphosphorylation between ADP and phosphoenolpyruvate for further generation of ATP and pyruvate, which is an irreversible process. Within nuclei, it acts as a protein kinase for reprograming tumor metabolism from OXPHOS toward aerobic glycolysis. This is for fueling tumor cell proliferation and migration [90]. It seems that a metabolic predilection is occurring here in order for prioritizing the fueling of tumor cells while restricting anti-tumor macrophages to have an access to such energy source. A proof of concept here is a study by Li and colleagues on the role of PKM2 in metabolic coordination of cancer cells. PKM2 is contributed to the coordination of glutamine and glucose metabolism in cancer cells in which the cells will activate the process of glutaminolysis upon encountering defective glycolysis, as a response to the inactivation of glycolysis-related enzymes, and PKM2 is a mediator of this shift in metabolic acquisition by the cells. Dimer of PKM2 facilitates such event, which defines a mechanism exploited by cancer cells in order to adapt well with the environment nearby [92] (Figure 3b).
Giant cell arteritis: what is new in the preclinical and early clinical development pipeline?
Published in Expert Opinion on Investigational Drugs, 2022
Patricia Harkins, Richard Conway
The Janus Kinase (JAK) family, namely JAK1, JAK2, JAK3, and TYK2, are a group of receptor associated tyrosine kinases pivotal in mediating downstream cytokine signaling and thus contributing to the pathogenesis of many immune-mediated pathologies [66]. They work by phosphorylating tyrosine residues on proteins, including on JAKs themselves (autophosphorylation) and also on adjacent molecules (transphosphorylation) including the signal transducers and activators of transcription (STAT) family [67]. The STAT family are a group of transcription factors which upon phosphorylation, translocate to the nucleus, bind DNA and drive gene transcription [66]. Many different molecules including interleukins, interferons, and growth factors, to name but a few, utilize this essential JAK/STAT pathway to mediate their effects through type 1 and type 2 receptors [67]. Thus the role of the JAK/STAT pathway and more specifically its inhibition through small molecule JAK inhibitors (Jakinibs) have garnered much interest in the area of inflammatory disorders, including GCA.
JAK inhibitors: special issue foreword
Published in Expert Review of Clinical Immunology, 2022
James Galloway, Fabiola Atzeni
The JAK inhibitor class selectively targets one or more of the homo- or heterodimeric intracytoplasmic signaling pathways that have central roles in intracellular signal transduction. In humans, the JAK pathways are a family of four protein structures: JAK1, JAK2, JAK3, and TYK2 [1–4]. Activation of a JAK pathway results in transphosphorylation that triggers signal transduction and activation of transcription (STAT) recruitment and subsequent downstream transcriptional responses, such as production of pro-inflammatory proteins like CRP. JAK signaling is highly organized, with cross talk existing between many other intracellular pathways and our understanding of these networks continues to grow. Dysregulation of JAK signaling is a feature of many diseases. Targeting the JAK pathway started out as a therapeutic option in the field of myeloproliferative disorders. The JAK2 Val617Phe mutation, which results in constitutive activation of the pathway, is found in over 50% of individuals with myelofibrosis and essential thrombocythaemia, and almost 100% of patients with polycythemia vera [5,6]. Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved for clinical use to treat myelofibrosis in 2011.