China
Africa
Explore chapters and articles related to this topic
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
ROS1 activates several downstream signaling pathways related to cell differentiation, proliferation, growth, and survival. It phosphorylates and activates predominantly STAT3, which is required for ROS1 anchorage-independent growth [87]. It also phosphorylates VAV2, which is a guanine-nucleotide exchange factor for Rho GTPases that regulates actin dynamics and gene expression [88]. It also activates the PI3K/AKT/mTOR signaling pathway [89, 90].
CBL Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
RAS proteins exist as an inactive GDP-bound form and an active GTP-bound form. Binding of a growth factor to receptor tyrosine kinase (RTK) induces RTK autophosphorylation and interaction with growth factor receptor-bound protein 2 (GRB2), which is bound to son of sevenless 1 (SOS1). As a guanosine nucleotide exchange factor (GEF), SOS1 facilitates conversion of inactive GDP-bound RAS to active GTP-bound RAS, which activates downstream signaling cascades (e.g., the MAPK/RAF/MEK/ERK pathway, the PI3K/AKT/mTOR pathway, and the Ral-GEF/TBK1/IRF3/3-NF-κB pathway).
Regulators of Signal Transduction: Families of GTP-Binding Proteins
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
If the release of GDP controls the activity of ras, what controls the off-rate of GDP? At this point we have no idea. The presence of factor(s) which serve the function of receptors for G-proteins or guanine nucleotide exchange factor(s) of protein synthesis is implicit in any model of ras function, but has yet to be identified. Studies of RAS functions in yeast have revealed the presence of a protein (cdc25) with a molecular weight of about 160,000 that is involved in the adenylate cyclase/RAS pathway and acts upstream of RAS (see below). This is a good candidate for a factor which may regulate the binding of guanine nucleotides to RAS proteins. The cDNA sequence of cdc25 does not contain membrane-spanning regions indicative of transmembrane receptors. Thus, if cdc25 is the activator of p21, it may not be analogous to the receptors that activate the oligomeric G-proteins. Then the question becomes what activates cdc25?
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
The main cause of prolidase deficiency is related to the PEPD gene and patients with this defect typically present recurrent infections, hepatomegaly and splenomegaly, which may cause thrombocytopenia [261]. Other defects in regulatory T cells due to mutations in DEF6 and IL2RG have been reported to cause autoimmune thrombocytopenia [237, 245]. DEF6/IBP/SLAT has been considered as a unique guanine nucleotide exchange factor for the Rho GTPase Cdc42 and Rac. DEF6 has contribute to TCR signaling and is phosphorylated by the tyrosine-protein kinases LCK21 and ITK [237]. Defects in T-cell helper differentiation, T-cell expansion and germinal center formation are some consequences of this deficiency [262]. So, the immune response may accompany thrombocytopenia in this disorder [14, 15, 19, 20]. Disrupt normal AIRE activity manifests autoimmune polyendocrine syndrome type 1 (APECED) lead to impaired AIRE protein. AIRE expression is activated in the thymus and known as a critical need to induce T-cell tolerance [263].
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
A potential alternative approach to RAS inhibition involves targeting proteins that regulate RAS. In particular, the guanine nucleotide exchange factor SOS1 has emerged as a viable target for the treatment of RAS-driven cancers. By preventing the SOS1-mediated loading of GTP onto RAS, RAS can be maintained in an inactive state. Through this mechanism, the overactivation of downstream signaling pathways and the corresponding unchecked cellular proliferation that is characteristic of RAS-driven cancers may be suppressed. Over the last decade, a considerable amount of effort has been devoted to the development of small molecules that modulate the activation of RAS by means of binding to SOS1. These efforts have culminated in the identification of an exploitable-binding pocket and the development of multiple series of small-molecule SOS1 inhibitors that bind to this pocket to affect the interaction of SOS1 with RAS (both mutant and WT) and modulate downstream signaling pathways. Several of these compounds have further demonstrated the ability to inhibit RAS-driven tumor growth in in vivo models, with one compound currently in phase I clinical trials.
Targeting the integrated stress response in ophthalmology
Published in Current Eye Research, 2021
Hsiao-Sang Chu, Cornelia Peterson, Albert Jun, James Foster
Under cellular stress, any of the above-mentioned kinases can phosphorylate Ser51 of eIF2α (peIF2α). This event causes the subunit to increase its affinity for the guanine nucleotide exchange factor, eIF2B.46 Once bound peIF2α inhibits the ability of the eIF2B to exchange GDP for GTP resulting in a decrease in the available pool of free GTP-eIF2 and decreasing the rate of translational initiation.33 The amount of eIF2B in the cell is significantly less than eIF2α so only a small increase in peIF2α can sequestrate all the available eIF2B and effectively shut down cap-dependent mRNA translation.48,49 This reduction of global protein synthesis via the 5ʹ cap-dependent mRNA translation serves a number of cytoprotective roles.37 In conditions of amino acid shortage50 or iron deficiency,51 it reduces the rate at which these nutrients are consumed, during viral infection it slows viral replication by impeding viral protein synthesis.52,53 While in ER stress, its activation decreases the rate of proteins entering the ER, thereby relieving the overburdened organelle.54