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Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
More recently, mechanisms involved in tyrosine kinase-mediated signal transmission have been elucidated to a sufficient degree to confirm direct involvement of receptor tyrosine kinases.59 The best characterized pathway involves direct activation of phospholipase C-γ-1 (PLC-γ-1) (Figure 5). Phos-pholipase C catalyzes the conversion of phospharidylinositol-4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3). Nishibe and co-workers60 were able to show that the addition of EGF to cells is followed rapidly by phosphorylation of PLC-γ-1 on tyrosine. More recently, Gold-schmidt-Clermont et al.61 showed that tyrosine phosphorylation of PLC-γ-1 increases activity with a complex of PIP2 and profilin. Profilin is a cytoplasmic actin binding protein which binds PIP2 with high affinity. Thus, the current working hypothesis states that PLC-γ-1 activation by the EGF receptor leads to IP3 production and release of profilin, which can interact with the cyto-skeleton (Figure 5). This may account, at least in part, for rapid effects of EGF on cell shape and motility.
Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
The regulation of the PLC-γ1 family has been elucidated in considerable detail. Kim et al.33 have determined the relative contributions made to PLC-γ1 activation by three tyrosine residues that are phosphorylated when PLC-γ1associates with the PDGF receptor in 3T3 cells. Substitution of Tyr771 with phenylalanine slightly enhanced the activation, but a similar substitution of Tyr1254 markedly decreased the extent to which the enzyme was activated by the PDGF receptor in these cells.33 An even stronger attenuation was caused by substituting Tyr783 with phenylalanine; the PLC-γ1 Tyr783Phe could associate with the PDGF receptor and was serine phosphorylated as a consequence, although no activation occurred. Thus, tyrosine residues 783 and, to a lesser degree, 1254 are those that contribute to the control of the activity of PLC-γ1, in intact cells.33 Interestingly, others have shown that mutant EGF and PDGF receptors, which fail to activate PLC-γ1 and to increase cytosolic calcium in vivo, effectively induced gene expression and mitogenesis.34 Taken together, these studies suggest that formation of receptor–SH-2 complexes are important in some, but not all, responses of cells to growth factors, and other parallel signaling pathways apart from PLC-γ1 activation may be necessary to mediate growth factor-induced mitogenesis.
Endotoxin Effects on Synthesis of Phosphatidic Acid and Phosphatidic Acid–Derived Diacylglyceride Species
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
In contrast, it now seems apparent that PA specifically enhances the activation of some PLC isoforms, particularly PLCγ associated with tyrosine-kinase receptor signaling, through changes in PLC conformation, possibly guaranteeing exposure of src homology type 2 (SH2) and pleckstrin homology sites for complex protein binding and hence activity recruitment, SH2 binding to the receptor, or signaling (1,2,28). Thus, membrane synthesis of PA from PC may have immediate stimulatory or permissive consequences in terms of signal transduction related to PI signaling (this should also be viewed as another possible locus in which PA may affect calcium currents, i.e., by regulating PLCγ-related synthesis of inositol trisphosphate [IP3], which in turn regulates IP3-sensitive Ca2+ channels in endoplasmic reticulum). Similarly, evidence has accumulated recently, suggesting the existence of a PL-activated protein kinase that is most sensitive to PA (1,29). Whether this represents a direct signal transduction kinase activated by PA or simply a membrane-associated kinase that has PL requirements remains unclear.
BCL11B depletion induces the development of highly cytotoxic innate T cells out of IL-15 stimulated peripheral blood αβ CD8+ T cells
Published in OncoImmunology, 2022
Hannes Forkel, Piotr Grabarczyk, Maren Depke, Sascha Troschke-Meurer, Stefan Simm, Elke Hammer, Stephan Michalik, Christian Hentschker, Björn Corleis, Lucie Loyal, Maxi Zumpe, Nikolai Siebert, Anca Dorhoi, Andreas Thiel, Holger Lode, Uwe Völker, Christian A. Schmidt
Besides changes in genes related to naivety and innateness in BCL11B knock-out, we observed a switch from PLCG1 to PLCG2 expression. Both genes encode for PLCγ enzymes, which are key nodes in cellular signal transduction and are of varying importance for different lymphocyte lineages.50 While PLCγ1 dominates in T lymphocytes, PLCγ2 is not expressed by human CD8+ T cells but is essential for NK cell cytotoxicity and innate immunity against malignant and virally infected cells.51 BCL11B knock-out led to a partial loss of PLCG1 and gain of PLCG2 expression accompanied by increased expression of FCER1G and LYN, two genes encoding proteins involved in the upstream events in the PLCγ signaling cascade (Figure 5(c)). The evidenced shift of transcriptome profile from naïve toward an innate phenotype was further supported by increased protein levels of the key innate transcription factors. The amount of PLZF protein encoded by the ZBTB16 gene was highly increased in BCL11B knock-out cells compared to controls. The helix-loop-helix inhibitor of differentiation ID2, essential for the normal development of NK cells,52 was also induced in BCL11B knock-out samples. Additionally, HOPX, a factor previously proven to be enriched in effector NK and effector CD8+ T cells compared to their naïve counterpart,53 demonstrated increased abundance after BCL11B knock-out in our study (Figure 5(d)).
BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient?
Published in Expert Review of Hematology, 2022
Sai Prasad Desikan, Sangeetha Venugopal, Alessandra Ferrajoli
Finally, resistance mechanisms to covalent BTKi are mediated by mutations to the BTK binding pocket at C481 and mutations to downstream effector proteins, in particular, PLCγ2 [51–53]. Novel reversible, non-covalent inhibitors in patients with C481S mutations overcome this resistance mechanism, as they bind at other sites within the binding pocket [47,48,53]. PLCγ2 mutations are believed to confer resistance to pirtobrutinib [54]. Interestingly, pre-clinical data suggest that nemtabrutinib has additional off-target inhibition of SYK and ERK, proteins that interact with PLCγ2, potentially still promoting BCR pathway inhibition, despite PLCγ2 mutations [55]. Although MS-553 is predicted to be effective in PLCγ2 and C481S mutated CLL based on pre-clinical data, studies with patient who have these mutations are still ongoing [56]. The combination of multiple targeted inhibitors addressing different proteins in the BCR pathway remains a potential avenue of therapy, as demonstrated in pre-clinical studies utilizing ibrutinib with a SYK inhibitor in MYD88 mutated lymphoma [57]. These combination regimens utilizing multiple different approaches are under study and may prevent the development of resistance.
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
The clustering of GPVI and CLEC-2 drives intracellular signaling cascades that lead to activation of platelets. GPVI is a single transmembrane protein belonging to the immunoglobulin family of receptors that is expressed in the membrane with the dimeric Fc receptor (FcR) γ-chain, with each chain having an immunoreceptor tyrosine-based activation motif (ITAM), characterized by two conserved YxxL sequences [29]. In contrast, the single transmembrane, lectin-like receptor, CLEC-2, has one YxxL sequence in its cytosolic tail, named a hemITAM (or hemi-ITAM) [30]. Clustering of GPVI or CLEC-2 leads to phosphorylation of the conserved tyrosines in the hemITAM or ITAM sequence by Src and Syk tyrosine kinases, leading to binding of the tandem SH2 domains in Syk and initiation of a downstream signaling cascade orchestrated through the protein adapter LAT. This acts as a binding template for other proteins facilitating a phosphorylation cascade, including various adapter and effector proteins, leading to activation of PI 3-kinase and PLCγ2 (Figure 1). PI 3-kinase generates the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) which binds to pleckstrin homology and SH2 domains. PLCγ2 generates the second messenger inositol 1,4, 5-trisphosphate (IP3) and 1,2-diacylglycerol, which release Ca2+ and activate protein kinase C, respectively.