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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.
Multiple endocrine neoplasia type 2
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Shc adaptor proteins have been shown to bind RET in vivo, which leads to activation of the RAS -MAP kinase (MAPK) pathway (Figure 3) (Asai et al., 1995; Santoro et al., 1995). The tyrosine residue Y1062 has been shown to play a significant role in She binding, among other adaptor molecules, as it is a multi-functional docking site (Asai et al., 1996). Y1062 appears to be a phosphorylation-dependent docking site for Shc and a phosphorylation-independent site for interaction with the membrane-anchored enigma through its LIM domain, the latter believed to play a role of positioning RET in the cellular membrane (Durick et al., 1996, 1998a). RET activation of the RAS-MAPK pathway is mediated by Shc and Grb2 or Grb2 alone.
REGULATORY MECHANISMS
Published in David M. Gibson, Robert A. Harris, Metabolic Regulation in Mammals, 2001
David M. Gibson, Robert A. Harris
In the* МАРК signal pathway the insulin-activated receptor tyrosine kinase phosphorv-late.s tyrosines on the adaptor protein MShcM, much like- the phosphorylation of IKS (Figure Ì.8). The activated She intermediate hinds to SH2 domains on a second adaptor protein called MGrb-2". On this adaptor protein another amino acid sequence domain, designated SI И ('Fahle Î.2), attracts proline-rich regions of the next signal transduction protein, "Sos", which in binding to Grb-2 becomes activated. Note in Figure J.8 an opportunity lor cross talk between the two signal trunk lines through the binding of the SI 12 segments on Grb2 with the phosphorylatcd tyrosines of 1RS molecules. Other
Origanum Sipyleum Methanol Extract in Combination with Ponatinib Shows Synergistic anti-Leukemic Activities on Chronic Myeloid Leukemia Cells
Published in Nutrition and Cancer, 2022
Cagla Kayabasi, Sunde Yilmaz Susluer, Tugce Balci Okcanoglu, Besra Ozmen Yelken, Zeynep Mutlu, Bakiye Goker Bagca, Cansu Caliskan Kurt, Guray Saydam, Cenk Durmuskahya, Husniye Kayalar, Ahmet Ozbilgin, Cigir Biray Avci, Cumhur Gunduz
We evidently know that the BCR-ABL1 oncogene is formed as a molecular result of t(9:22), and constitutive kinase activity of the chimeric BCR-ABL1 oncoprotein supports the growth advantage of leukemic cells (10, 11, 41). Activated BCR-ABL1 generates docking sites for adapter proteins CRKL and GRB2 (42). GRB2 activates the MAPK pathway through SOS/RAS/RAF1/MEK1/ERK1 axis (43). Also, the PI3K/Akt pathway is activated by BCR-ABL1 directly or indirectly through GRB2/GAB2/Akt or CRKL/CBL/PI3K/Akt cascades (44, 45). In addition, BCR-ABL1 activates STAT5 and Myc directly or indirectly through JAK2 (45, 46). Among these downstream targets of BCR-ABL1, we reported that CRKL, GRB2, AKT1, MYC, STAT5B, and STAT5A were down-regulated in K562 cells during p-OSM treatment. Previous studies proved that BCR-ABL1 blocks the activity of tumor suppressor PP2A by inducing the expression of SET, the PP2A inhibitor (47). C/EBPα, one of the transcription factors involved in the formation of myeloid cells, is a critical target in CML disease progression (48, 49). BCR-ABL1 represses the expression of C/EBPα by activating the RNA-binding protein hnRNP E2, the negative regulator of C/EBPα (49). Through our experiments, we also confirmed that p-OSM treatment up-regulated the expressions of PP2A and CEBPA significantly. That is why we suggest that BCR-ABL1 downstream signaling impacted by the combination of ponatinib and OSM is strictly associated with the pair’s anti-proliferative properties.
From bench to bedside: bridging the gaps in best practices for real-world chronic myeloid leukemia care
Published in Expert Review of Hematology, 2022
Giovanni Manfredi Assanto, Emilia Scalzulli, Ida Carmosino, Maurizio Martelli, Massimo Breccia
The occurrence of resistance to TKIs, sustained by dormant leukemic stem cells developing new survival pathways, highlights the necessity to investigate off BCR::ABL1 therapeutic target which could, eventually in combination, eradicate the disease or maintain response to TKIs. GRB2 is a transduction protein involved in the activation of alternative signaling for RAS/MAPK, JAK/STAT promoting cell survival. BP1001 is an antisense nucleotide of GRB2 incorporated in liposomal formula which inhibits its expression. It was tested on phase 1/2 trials in combination with dasatinib showing not sufficient efficacy. Other target in RAS pathways is the farnesyl transferase, responsible for intracellular signal transduction. Also compound targeting this enzyme failed in combination with imatinib to achieve promising results. Same poor results were obtained in trials testing PI3K inhibitor (idelalisib) and mTOR inhibitors (everolimus, sirolimus) [77,78]. Given the involvement of JAK/STAT pathway, the combination approach of ruxolitinib with TKI is currently under investigation in different clinical trials (anonymized) [79,80]. Following similar rationale, BCL2 inhibitor venetoclax is currently being evaluated in combination with dasatinib (phase II (anonymized). Many other molecules and pathway inhibitors were or are currently in preclinical studies trying to overcome resistance and may constitute future therapeutic options in CML [71,81–83].
The roles of epidermal growth factor receptor in viral infections
Published in Growth Factors, 2022
Stimulation of EGFR by ligands leads to the activations of a number of intracellular signal transduction pathways, including RAF/MEK/ERK1/2, JAK/STAT, phospholipase C (PLCγ), protein kinase C (PKC), and phosphatidylinositol 3-kinase (PI3K)/AKT (Figure 1). RAF/MEK/ERK1/2 pathway is one the best characterised signalling cascade induced by EGFR (Fehrenbacher, Bar-Sagi, and Philips 2009). Ligand-induced activation of EGFR leads to recruitment of Grb2 adaptor protein and formation of Grb2/SOS protein complex. This complex activates small GTPase, RAS by catalysing the exchange of GTP for GDP in the guanine nucleotide–binding site of RAS. GDP-bound RAS recruits RAF serine/threonine kinase to the cell membrane, which in turn activates the dual specificity tyrosine/threonine kinase, MEK via phosphorylation of multiple serine residues. Activated MEK phosphorylates ERK1/2 protein, which then translocate to the nucleus and regulate expressions of gene that related to cell proliferation, cell differentiation, stress response and apoptosis (Roberts and Der 2007; Li et al. 2016).