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Cell Adhesion Molecules in Mast Cell Adhesion and Migration
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Harissios Vliagoftis, Dean D. Metcalfe
The effector pathways by which receptor tyrosine kinases regulate cell-matrix adhesion have been studied in more detail in mast cells using wild-type and mutant forms of the PDGF receptor. This receptor is closely related to c-kit, is expressed in mast cells, and is as potent as c-kit in stimulating adhesion to fibronectin (27). Adhesion stimulated through the PDGF receptor is regulated through two independent pathways involving phosphatidyl-inositol 3 kinase (PI3K) and phospholipase C-gamma 1 (PLC gamma)-protein kinase C. Receptors mutated so that they could not associate with PI3K and PLC gamma continued to stimulate mast cell growth, but not adhesion, indicating a crucial role for these molecules in regulating adhesion rather than cell growth (27). In another approach, transfection of mast cells from Wsh/Wsh mice that do not express endogenous c-kit, with wild-type or mutated murine c-kit, revealed that Y719, necessary for the association of c-kit with PI3-kinase, is also necessary for the induction of adhesion through SCF (28). This mutation, however, impaired only partially the SCF-induced proliferation and survival of mast cells.
Properties of GAP Proteins
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Human pl20-GAP cDNA clones were first obtained from a placenta cDNA library in Frank McCormick’s laboratory.2 The deduced amino acid sequence revealed a very high homology (96%) to the previously isolated bovine GAP.3,4 The most common form of human GAP (type I GAP) is present in all tissues and cells thus far examined.21 A schematic representation of its structure is shown in Figure 1. Different domains of the protein have been defined through both experimental and theoretical analysis. The carboxyl terminus of the molecule contains the catalytic domain, as shown by the fact that a truncated form, consisting in the last 344 amino acids, retains full GTPase-stimulating activity.22 This is the most conserved sequence (98% homologous to bovine GAP2,3, NF-120 and IRA1 and IRA215). The rest of the molecule is most likely the target for regulation of its activity. This has been deduced through analysis of its sequence: three src homology (SH) regions (two SH2 and one SH3 regions) were identified, first in bovine, and then in human GAP.4,24 These SH2 and SH3 domains are known to be regulatory sequences of different nonreceptor tyrosine kinases (src, fps, abl, etc.) and some cytosolic proteins like phospholipase C-gamma and crk oncogene.23,73 These domains seem to be implicated in the interaction of GAP with tyrosine-phosphorylated molecules,73 as it will be discussed below.
Pharmacogenetics of Mood Disorders: Is there a Future?
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Lerer Bernard, Agid Ofer, Macciardi Fabio
In spite of the fact that mode of inheritance has not been established, linkage studies of bipolar disorder, using lithium responsiveness to refine the phenotype, have been performed. In one study that used both association and linkage approaches, a polymorphism in the phospholipase C gamma-1 genes was examined. In a case control sample, modest association with lithium-responsive bipolar disorder was observed (OR = 1.88). A linkage study in a family sample also showed some support (lod = 1.45; p = 0.04) [39]. Turecki and colleagues [40] have completed a whole genome scan of 21 families (247 subjects, 108 affected) in which regions on chromosome 6, 7, 15, 21, and 22 yielded lod scores suggestive of linkage. In the chromosome 15q14 region, a lod score of 3.46 (p = 0.000014) was obtained with the marker ACTC and on chromosome 7q11.2 and a lod score of 2.62 (p = 0.0001) with the marker D7S1816. Using responsiveness to lithium as the phenotype, the highest lod score was 1.53 (p = 0.003) for the marker D7S1816. This group has also conducted association studies comparing lithium-responsive patients and controls. Besides the modestly positive association for phospholipase C gamma-1 noted above, negative results were obtained for several candidate genes including MAOA, CRN, proenkephalin, and genes related to GABA function [30].
Bruton’s tyrosine kinase as a promising therapeutic target for multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2023
Darius Saberi, Anastasia Geladaris, Sarah Dybowski, Martin S. Weber
After antigen binding to the B cell receptor (BCR), Lck/Yes novel tyrosine kinase (Lyn), a member of the SRC kinase family phosphorylates the Igα and Igβ immunoreceptor tyrosine-based activation motifs (ITAMs), which then binds spleen tyrosine kinase (SYK). In the next step, SYK gets phosphorylated by Lyn and BTK is recruited from the cytosol to the plasma membrane [75]. In general, activation of BTK is characterized by phosphorylation at the position Y551 of BTK. This promotes the catalytic activity of BTK and subsequently results in its autophosphorylation at the position Y223 in its SH3 domain [71]. Active BTK phosphorylates phospholipase C gamma 2 (PLCγ2). Consequently, PLCγ2 generates two second messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The activation of calcium channels by IP3 results in a transport of nuclear factor of activated T cells (NFAT) into the nucleus. The pathway of nuclear factor ‘kappa-light-chain-enhancer’ (NF-κB) of activated B cells and mitogen-associated protein kinase (MAPK) is activated by DAG. The expression of several genes that are essential for B cell survival and proliferation chemokine and cytokine expression is regulated by NFAT and NF-κB (Figure 1). In summary, this complex cascade leads to an increase in survival and accelerates the proliferation of B cells, and therefore highlights the pivotal role of BTK in B cells [76].
Astragalus injection ameliorates lipopolysaccharide-induced cognitive decline via relieving acute neuroinflammation and BBB damage and upregulating the BDNF-CREB pathway in mice
Published in Pharmaceutical Biology, 2022
Ke Liu, Guoran Wan, Ruhong Jiang, Li Zou, Dong Wan, Huifeng Zhu, Shan Feng
A recent review summarized that BDNF was involved in the formation of different types of memories and also critical for maintaining the long-lasting storage of information in the hippocampus (Kozisek et al. 2008). It was similar to another report showing that the hippocampus-specific deletion of BDNF in adult mice impaired spatial memory and caused extinction of aversive memories (Heldt et al. 2007). BDNF binds to its high-affinity receptor TrkB, triggering the activation of one or more of three major signalling pathways, such as CaMKIIα, phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma (PLC-γ), and extracellular signal-regulated kinase 1/2 (ERK1/2), regulating certain forms of synaptic plasticity, including long-term potentiation and affecting synaptic transmission (Koike et al. 2013; Adachi et al. 2017; Xenos et al. 2018). The molecular docking results indicated that Astragalus injection could upregulate BDNF expression and activate its downstream pathways TrkB/CaMKIIα/CREB, thus produced neuroprotection with resulting improvement in memory function.
Approved and emerging Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Alycia Hatashima, Mehdi Karami, Mazyar Shadman
BCR signaling plays a critical role in healthy and aberrant B lymphocyte differentiation, proliferation, and survival [1]. Activation of BTK following antigen stimulation of the BCR is a key driver of B-cell malignancies, including CLL and thus, an attractive therapeutic target. CLL proliferation occurs predominantly in secondary lymphoid organs; in lymph nodes, the tissue microenvironment supports and interacts with CLL cells. BCRs bind to cell-surface antigens on ‘nurselike cells’ or macrophages, various soluble antigens, and B-cell receptors on neighboring CLL cells inducing downstream signaling cascades involving non-receptor tyrosine kinases: LYN, spleen tyrosine kinase (SYK), PI3K, and BTK. The BTK pathway involves the subsequent activation of phospholipase C gamma 2 (PLCG2) and generation of second messengers which promote transcriptional activation though extracellular signal-regulated kinases and nuclear factor κB (NF-kB) [37,38]. In addition, BTK, SYK, and PI3K are responsible for the signal transmission and function of chemokine receptors, including CXCR4 and CXCR5, and adhesive interactions between integrins such as very-late antigen 4 and vascular cell adhesion molecule 1 [1,37,39]. Small-molecule inhibitors targeting these kinases interfere with CLL-cell homing and migration to lymphoid tissues, thereby shifting cells to the peripheral blood causing ‘redistribution lymphocytosis.’