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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
The second largest insulin signaling pathway similarly starts with autophosphorylation sites in SH domains on the IR, which then binds and phosphorylates the protein SHC. Following the binding of Growth factor receptor-bound protein 2 (GRB2), GRB2 then recruits and activates the guanine nucleotide exchange factor Son of sevenless homolog (SOS). Activated SOS promotes the dissociation of guanosine diphosphate (GDP) from the Ras GTPase which allows Ras to bind guanosine triphosphate (GTP) and become activated. GTP-bound Ras can then interact with the proto-oncogene serine/threonine-protein kinase c-Raf, which finally activates the serine/tyrosine/threonine Mitogen-activated protein kinase (MEK, also known as MAP2K or MAPKK). MEK in turn phosphorylates and activates the serine/threonine kinases mitogen-activated kinase (MAPKs; originally named “extracellular signal-regulated kinase” (ERKs)). This sequence of kinases is a classic example of a protein kinase cascade, where the numerous constituents allow for feedback regulation and signal amplification.
Targeting BCR-ABL in Chronic Myelogenous Leukemia
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Activation of mitogenic signaling. Autophosphorylation of Y177 provides a docking site for GRB-2. It binds to the SOS protein and stabilizes Ras in its active GTP-bound form. Secondly, phosphorylation of stat transcription factors (stat1 and stat 5) has been reported in several BCR-ABL positive cell lines and in primary CML cells [19]. Thirdly, PI3 kinase activity is required for the malignant transformation of CML cells. BCR-ABL forms multimeric complexes with the PI3 kinase through CBL, and adaptor molecules CfíÆ-like (CRKL) protein [19, 20]. The BCR/ABL oncogene may be physically linked to the focal adhesion-associated protein paxillin in hematopoietic cells by CRKL [21].
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).
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
However, other KRAS mutants like KRASG12V or KRASG12D hinder the possibility of developing covalent inhibitors, thus driving the need to exploit widely applicable or pan-RAS inhibition strategies. These inhibitors bind to the interface between KRAS and effector proteins (RAF, PI3K) or regulators (SOS), represented by the early discovery of DCAI, Kobe 0065, and VU0460009 resulted from HTS and virtual screening[100]. In the past five years, the development of CADD and FBDD has facilitated the discovery of more novel RAS inhibitors, including the pan-RAS inhibitor compound 3144, BI-2852 and so on (Figure 3c) [10,88,89]. Predominantly, the pan-RAS inhibitor BI-1701963 targeting KRAS-SOS interaction officially entered the clinical study in 2020, demonstrating a breakthrough of targeting a wide panel of KRAS-driven cancers.
Expression and clinicopathological significance of Nck1 in human astrocytoma progression
Published in International Journal of Neuroscience, 2019
Ravindra Pramod Deshpande, Manas Panigrahi, Chandra Sekhar Y.B.V.K, Phanithi Prakash Babu
Nck1 is well characterized family of adaptor protein with SH2/SH3 domains. Sos has been shown to be one of the interacting partner of Nck [18] resulting in Ras activation [19]. Nck1 is shown to play a role in axonal guidance and have been overexpressed in murine colon carcinoma cell lines CT51, CT26, and in human breast cancer cell lines MCF7, T47D. Nck2, a homologue of Nck1 is reported to promote melanoma cell migration and invasion by modulating actin cytoskeleton [20]. Nck1 expression is reported prevent tunicamycin induced CHOP expression and apoptosis in Hep G2 and MCF-7 cell lines, thus playing a role in counteracting deleterious effect of ER stress in cancer cell survival [21]. Recent report reveals that NCK1 promotes metastasis and angiogenesis in colorectal cancer and works as one of the downstream target of STAT3 [22]. Expression profile and prognostic significance of Nck1 in astrocytoma pathology is not assessed. Considering the available information on biology of Nck1 expression, we evaluated expression profile and prognostic significance of Nck1 in astrocytoma progression.
KRAS mutations in metastatic colorectal cancer: from a de facto ban on anti-EGFR treatment in the past to a potential biomarker for precision medicine
Published in Expert Opinion on Biological Therapy, 2021
Dahna Coupez, Pauline Hulo, Yann Touchefeu, Marc G Denis, Jaafar Bennouna
RAS is a guanine nucleotide-binding protein belonging to the G protein family. Its binding to guanosine diphosphate (GDP) or guanosine triphosphate (GTP) helps distinguish inactive and active forms [30]. The four isoforms of RAS, KRAS (4a and 4b), NRAS, and HRAS, differ slightly in their amino acid sequences, mainly in the C-terminal region (hypervariable region), which is anchored to the plasma membrane (Figure 3). The highly conserved G-domain contains the nucleotide-binding site and switch I and II regions. The conformational modifications of these two flexible components guide the shift between GTP-RAS and GDP-RAS. Switch I and II regions also interact with the guanine exchange factor (GEF) and GTPase activating protein (GAP). GEF removes GDP from the nucleotide-binding site for GTP binding. GAPs promote the GTPase activity of RAS, releasing a phosphate group from GTP to GDP [31]. Substitutions at residues 12, 13, or 61 prevent the association of GAPs with KRAS and maintain KRAS in its active form (Figure 4) [32]. Interestingly, the G12C substitution, contrary to other substitutions of G12 or G13, does not fully remove intrinsic GTPase activity [33]. The GDP-KRASG12C protein still persists and remains sensitive to GEFs. Son of Sevenless (SOS) is a GEF that forms an interface with an adaptor protein, GRB2, and a tyrosine phosphatase, SHP2, which is preliminarily captured and activated by the transmembrane receptor tyrosine. The constitutive activation of RAS, secondary to hotspot mutations, that is, at codons 12, 13, and 61, provides the original source for the downstream effectors [34].