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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The extracellular EGFR dimerization event stimulates the intracellular protein-tyrosine kinase signaling cascade via autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR. This autophosphorylation causes downstream activation and signaling through several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades including the MAPK, Akt, JNK, PI3K/AKT, and K-RAS/B-RAF/MEK/ERK pathways which ultimately lead to DNA synthesis. The resulting gene products are known to be associated with cell proliferation, migration, and adhesion.
p21ras and Receptor Signaling
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Boudewijn M. Th. Burgering, Johannes L. Bos
GAP was originally discovered as a cytosolic protein with an approximate molecular weight of 120 kDa.44 The GAP coding sequence has been cloned and its predicted amino acid sequence revealed few clues as to its function.45,46 It showed the presence of SH2 (src homology) and SH3 domains. SH2 domains are found in nonreceptor tyrosine kinases {src, yes, etc.), phopsholipase C-γ, phosphatidylinositol-3-kinase, and the crk oncogene.47 The SH2 domains are probably involved in the interaction with phosphotyrosine-containing domains, either intra- or intermolecularly,48,49 Deletion analysis revealed that the C terminal part (334 amino acids) of GAP is sufficient for the GTPase activating function and that the N terminal part, including the SH2 and 3 domains, probably fulfills a regulatory function.50
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A subfamily of SH2 domains is found specifically in protein-tyrosine phosphatases.468 Activation of these enzymes depends on tyrosine phosphorylation,469 and tyrosine phosphatases containing SH2 domains may be a target of tyrosine kinases. One of these enzymes, Syp, contains two SH2 domains and is rapidly phosphorylated on tyrosine in EGF- and PDGF-stimulated cells.470 Syp exhibits homology to the product of the corkscrew (csw) gene of Drosophila, which is required for signal transduction downstream of the Torso receptor tyrosine kinase of the insect.471 The Syp gene is widely expressed throughout mouse embryonic development as well as in adult mouse tissues. The activity of some tyrosine phosphatases may link growth factor receptors and other signaling cellular proteins with tyrosine kinase activity for the regulation of signal transduction and other related functions through phosphorylation/dephosphorylation of tyrosine.
Design, synthesis, and in vitro evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Patrik Oleksak, Miroslav Psotka, Marketa Vancurova, Olena Sapega, Jana Bieblova, Milan Reinis, David Rysanek, Romana Mikyskova, Katarina Chalupova, David Malinak, Jana Svobodova, Rudolf Andrys, Helena Rehulkova, Vojtech Skopek, Pham Ngoc Lam, Jiri Bartek, Zdenek Hodny, Kamil Musilek
The STAT3 protein structure is characterised by four domains involved in oligomerisation, binding to DNA, and transactivation activity, and a Src homology 2 (SH2) domain mediating phosphorylation-dependent dimerisation. The SH2 domain contains tyrosine 705 (Y705), which is phosphorylated in response to extracellular signalling by kinases of the Jak and Src families. STAT3 proteins with phosphorylated Y705 (pY705) form dimers via reciprocal binding of SH2 domains and they are further translocated into the nucleus to bind to specific DNA response elements. STAT3 are both activators and repressors of hundreds of genes, including cell cycle regulators MYC and CCND1 and anti-apoptotic BCL-2 family genes BCL2, BCL2L2 (BCL-W), BCL2L1 (BCL-XL), MCL1, and BIRC5 (survivin; reviewed in refs.4,5).
New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ahmed Elkamhawy, Eslam M. H. Ali, Kyeong Lee
The strcuture of Lck has the typical backbone found in all members of the Src kinase family (Figure 1); an N-terminal site (SH4 domain), SH3 and SH2 domains, a catalytic domain at the carboxy terminal (SH1 domain), and a short C-terminal tail17–19. The C-terminal lobe contains the activation loop (alpha-helix) which forms the phosphorylation site. Both SH2 and SH3 domains are folded to be involved in protein-protein interactions responsible for the regulation of Lck activity and signal transmission; while the main function of SH2 domain is to regulate interactions with phosphotyrosine containing elements, the SH3 domain regulates interactions with proline rich elements. The SH4 domain contains a glycine and two cysteine residues, which are myristoylated and palmitoylated, respectively, to target Lck to the plasma membrane.
Role of co- and post-translational modifications of SFKs in their kinase activation
Published in Journal of Drug Targeting, 2020
Mei-Lian Cai, Meng-Yan Wang, Cong-Hui Zhang, Jun-Xia Wang, Hong Liu, Hong-Wei He, Wu-Li Zhao, Gui-Ming Xia, Rong-Guang Shao
SH2 domains are a 100 amino acid modular unit that recognises and binds to tyrosyl-phosphorylated sequences of target proteins, thereby mediating the intracellular interactions of Src and its target proteins. In SFKs, the SH2 domain binds to the phosphorylated C-terminal tail of SFKs and then restrains SFKs in an inactive conformation, thereby inhibiting the exposure of the tyrosine kinase domain of SFKs. When the SH2 domain is bound by ligands from other proteins, such as focal adhesion kinase (FAK) and CRK-associated substrate (CAS) [67], the inactive conformation is destroyed and the kinase domain can be exposed, and correspondingly, SFKs are activated. Recently, there have been some reports that uncovered tyrosine phosphorylation in the SH2 domain play an important role in SFKs regulation.