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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.
Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
In addition to interaction with kinases, FAK may transduce signals through integrin-dependent interaction with adapter proteins such as Grb2 (localized to FAK residue Y925), SOS, and p130Cas (Cas) (150–152). Adapter proteins, which are small proteins composed almost exclusively of SH2 and SH3 domains (66) and which have no intrinsic kinase activity, may link FAK to the Ras pathway. SOS is a guanine nucleotide exchange factor (GNEF) that functions by converting inactive Ras-GDP to active Ras-GTP (153). Cas (Crk-associated tyrosine kinase substrate) is found in FACs and is likely phosphorylated by FAK and Src. Cas may serve as a docking protein that recruits additional signaling molecules, including Crk, to focal adhesions following integrin activation. Crk, which contains both SH2 and SH3 domains and may bind to C3G, a putative GNEF for Ras (152,154), has also been shown to associate with tyrosine-phosphorylated paxillin through its SH2 domain (155).
Noonan Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SOS1 (son of sevenless homolog 1) gene consists of 23 exons and encodes a 150-kd multidomain protein (SOS1) that functions as a RAS-specific guanine nucleotide exchange factor (GEF), stimulating the conversion of RAS from the inactive guanosine diphosphate (GDP)-bound form to the active guanosine triphosphate (GTP)-bound form. Structurally, SOS1 comprises a RAS-GEF domain, a conserved histone-like fold, Dbl homology (DH) and plekstrin homology (PH) domains, a helical linker, a RAS exchange motif (REM), and a proline-rich region. Binding of growth hormone to receptor tyrosine kinase (RTK) recruits SOS1 to the plasma membrane, which then converts RAS-GDP to RAS-GTP. Affecting 10%–15% of Noonan syndrome patients, SOS1 missense mutations (often located in codons encoding residues responsible for stabilizing the protein in an inhibited conformation) destabilize the DH domain and disrupt the autoinhibition of SOS1 RasGEF activity, contributing to increased and prolonged RAS activation and downstream signaling.
Small molecule Son of Sevenless 1 (SOS1) inhibitors: a review of the patent literature
Published in Expert Opinion on Therapeutic Patents, 2021
Severin K. Thompson, Andreas Buckl, Alexander G. Dossetter, Ed Griffen, Adrian Gill
RAS family proteins such as KRAS, NRAS, and HRAS are small GTPases that exist in either a functionally active ‘RAS(ON)’ state, in which they are bound to GTP, or an inactive ‘RAS(OFF)’ GDP-bound state (Figure 1) [1,2]. RAS proteins themselves have weak intrinsic GTPase activity and correspondingly slow inactivation. Binding of GTPase activating proteins (GAPs) such as Neurofibromin 1 (NF1) increases the GTPase activity of RAS-family proteins, thereby promoting the generation of inactive GDP-bound RAS [3–7]. The binding of guanine nucleotide exchange factors (GEFs) such as Son of Sevenless 1 and 2 (SOS1 and SOS2) [7–18] promotes the release of GDP from RAS which enables the binding of cell-abundant GTP [19]. When in the active GTP-bound state, RAS-family proteins are capable of engaging downstream effector proteins such as CRAF and phosphoinositide-3-kinase (PI3K) to initiate myriad cellular signaling pathways such as the RAF-MEK-ERK [20] and PI3K-AKT-mTOR [21] pathways, which are critical to cellular survival and proliferation.
The MAP kinase signal transduction pathway: promising therapeutic targets used in the treatment of melanoma
Published in Expert Review of Anticancer Therapy, 2020
Erin McClure, Michael J Carr, Jonathan S Zager
The MAPK pathway regulates cell growth and proliferation of melanocytes. Constituently activating mutations in this pathway are key to oncogenic pathogenesis in many cancers, including melanoma [18,19]. The MAPK pathway begins with cell wall receptor tyrosine kinase (RTK) activation/dimerization in response to the binding of an extracellular ligand. Activated RTKs recruit growth factor receptor-bound protein 2 (GRB2) and Son of Sevenless (SOS1) adaptor proteins, which in turn activate a RAS G-protein (encoded by HRAS, NRAS, KRAS, etc.) via GTP binding. RAS activates the serine/threonine kinase RAF (encoded by ARAF, BRAF, and CRAF), RAF phosphorylates tyrosine/threonine kinase MAPK kinase (MEK), and MEK subsequently activates ERK (extracellular signal-regulated kinase). Downstream signaling from ERK leads to increased proliferation and resistance to apoptosis of melanoma cells. [18,19]
Enhanced expression of son of sevenless homolog 1 is predictive of poor prognosis in uveal malignant melanoma patients
Published in Ophthalmic Genetics, 2019
The Ras ERK pathway has been demonstrated to be involved in cell growth and differentiation and has been studied extensively (7). Receptor activation followed by son of sevenless homolog 1 (SOS1) recruitment was one of the mechanisms of the Ras ERK pathway activation under physiological and pathological conditions (8). SOS1, encoded by the SOS1 gene in humans (9), is a guanine nucleotide exchange factor which could regulate Ras activity by GDP/GTP exchange (8,10–12). Function mutations and/or upregulation of the SOS1 gene have been previously reported to be related to gingival fibromatosis type 1 (13) and noonan syndrome type 4 (14). Moreover, the over-expression of SOS1 as well as a role in prostate cancer aggressiveness has been demonstrated in African-American male-derived primary prostate cancer epithelial cells (15). These reports suggested that SOS1 possesses the potential to be a target for cancer treatment. However, little is known about the role of SOS1 in UM tumorigenesis and development at present. As activation of the MAPK signaling pathway commonly participates in the development of UM (16) and SOS1 is involved in the activation of this pathway, we hypothesize that SOS1 might play an important role in the progression of UM.