Protein Phosphorylation
Enrique Pimentel in Handbook of Growth Factors, 2017
Tyrosine kinase activity is intrinsic to the receptors for certain growth factors.15-19 The cell surface receptors for insulin, IGF-I, EGF, FGF, NGF, HCGF, PDGF, and CSF-1 possess this type of activity. Activation of the receptor tyrosine kinase upon growth factor binding to its surface receptor is an important signaling transduction mechanism across the cell membrane. In addition to growth factors, a number of hormones, regulatory peptides, mitogens, neurotransmitters, and other extracellular signaling agents use a similar transductional mechanism. Phosphorylation of specific tyrosine residues is necessary, for example, for T-cell receptor-mediated signal transduction.40 The signaling mechanisms associated with activation of receptor tyrosine kinases directly result in the phosphorylation of various cellular proteins, including enzymes. These mechanisms may interact with other transductional mechanisms such as those represented by activation of phosphoinositide breakdown, intracellular mobilization of calcium, and activation of protein kinase C.41 An important connection exists between cell surface receptor tyrosine kinases and intracellular signaling pathways through the activation of Ras proteins.
The management of venous malformations
Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Fedor Lurie, Thomas W. Wakefield, Monika L. Gloviczki in Handbook of Venous and Lymphatic Disorders, 2017
Although the etiology of CVMs remains to be elucidated, data from relatively recent studies suggest that the pathophysiologic mechanisms responsible for the formation of CVMs are caused by dysfunctions in the signaling process(es) responsible for the regulation of the proliferation, differentiation, maturation, adhesion, and apoptosis of vascular cells during the development of the vascular system.10 Vessel development occurs in two different ways: vasculogenesis and angiogenesis.11 The exact mechanisms through which these processes occur remain largely unknown and have just recently begun to be unveiled. Vasculogenesis refers to the process by which endothelial cells are differentiated de novo from mesodermal precursors. It occurs only during embryonic development. In angiogenesis, new vessels are formed from pre-existing ones by budding (sprouting), splitting (intussusception), and fusion (intercalated growth). These new vessels that are formed by angiogenesis (the so-called juvenile system) evolve into mature vessels by the processes of maturation and remodeling.12 These complex processes involve several receptor tyrosine kinases. Some of these receptors and their ligands have been identified (i.e., vascular endothelial growth factors and Tie1 and Tie2).13
Chemical– and Drug–Receptor Interactions
Frank A. Barile in Barile’s Clinical Toxicology, 2019
The receptor tyrosine kinase consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. This class of receptor is associated with signaling by insulin, transforming growth factor-αα (TGFαα), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and many other trophic hormones. Ligand (hormone) binding to the receptor results in receptor dimerization, which triggers the tyrosine kinase activity in the intracellular domain. This causes autophosphorylation of the receptor and the induction of signal transduction cascades implicated in cell proliferation and survival. Figure 11.2 illustrates the mechanism of activation of the EGF receptor, a representative tyrosine kinase receptor.
Unveiling Taenia solium kinome profile and its potential for new therapeutic targets
Published in Expert Review of Proteomics, 2020
Naina Arora, Anand Raj, Farhan Anjum, Rimanpreet Kaur, Suraj Singh Rawat, Rajiv Kumar, Shweta Tripathi, Gagandeep Singh, Amit Prasad
Tyrosine kinases are classified as receptor tyrosine kinase and cytoplasmic tyrosine kinase based on the presence or absence of transmembrane domains. It is the third most abundant kinase in T. solium with 34 sequences; representing six receptor kinase families and nine cytoplasmic kinase families (supplementary 7). The receptor tyrosine kinases are involved in transmembrane signaling; the signaling is mediated by three domains present: extracellular domain, transmembrane domain, and an intracellular domain which carries catalytic center. On ligand binding, the receptor dimerizes and undergoes conformational change that relays signaling. This class consists of EGFR, FGFR, InsR, etc., which participate in growth, development, and metabolism [53]. On the contrary, cytoplasmic tyrosine kinases are involved in signaling to nucleus.
Synergistic Effects of Nobiletin and Sorafenib Combination on Metastatic Prostate Cancer Cells
Published in Nutrition and Cancer, 2019
Gamze Guney Eskiler, Asuman Ozkan Deveci, Cemil Bilir, Suleyman Kaleli
Receptor tyrosine kinases (RTKs) and their cellular signaling pathways play a major role in cell growth, cell cycle, cell migration, cell differentiation, and cell metabolism. Therefore, aberrant activation of RTK signaling pathways is associated with cancer development and metastasis. In recent years, RTK inhibitors, including imatinib, gefitinib, erlotinib, sunitinib, sorafenib (SOR), pazopanib, and nilotinib, have been developed to target RTKs for treatment of different cancer types (lung, breast, prostate cancer, hepatocellular carcinoma, etc.) (7–9). SOR is an oral multi-kinase inhibitor and approved by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma patients. Additionally, further clinical investigations are conducted in treatment of different cancer types (breast, prostate, myeloid leukemia, glioma, pancreas, and liver cancer). In phase II clinical studies, SOR demonstrates potential benefits compared with conventional chemotherapy in patients with metastatic or recurrent hormone-refractory prostate cancer. However, the results of clinical trials are not satisfactory due to SOR-related side effects (10–14).
Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings
Published in Expert Opinion on Drug Safety, 2019
Kristy Kummerow Broman, Lesly A Dossett, James Sun, Zeynep Eroglu, Jonathan S Zager
Activating mutations of the MAPK pathway – a regulator of cellular growth and proliferation – are key to the pathogenesis of most cutaneous melanomas [19,20]. MAPK signaling is initiated when extracellular ligands bind to specific membrane-bound receptor tyrosine kinases. Subsequent recruitment and activation of the guanosine triphosphatase RAS (rat sarcoma; encoded by HRAS, NRAS, and KRAS) result in a cascade of phosphorylation events involving the serine/threonine kinase RAF (encoded by ARAF, BRAF and CRAF). Phosphorylation of MAPK kinase (MEK) by RAF activates its only known substrate, ERK (extracellular signal-regulated kinase). Downstream signaling produces oncogenic cell proliferation and escapes from apoptosis [19,20].
Related Knowledge Centers
- ERBB
- Genome
- Growth Factor
- Cancer
- Cytokine
- Cell Surface Receptor
- Hormone
- Tyrosine Kinase
- Gene
- NON-Receptor Tyrosine Kinase