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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.
B Cells and Humoral Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Many of the biochemical steps in B cell activation are still being elucidated. With respect to signalling via the Ig receptor, the PTK syk may initially phosphorylate Ig-α and -β, permitting their interaction with a host of other PTKs such as blk, fyn, lck, and lyn (Figure 5–13). Phospholipase C γ (PLCγ) then associates with the receptor complex, its activity is further regulated by a G (GTP-dependent) protein. PLC cleaves phosphatidylinositolbisphosphate (PIP2) yielding inositoltriphosphate (IP3) and diacylglycerol (DAG). DAG is essential for the action of protein kinase C (PKC). IP3 causes release of intracellular calcium stores and influx of extracellular calcium. PKC and calcium-dependent kinases in turn phosphorylate other membrane proteins, other kinases, and transcription factors, leading to all of the phenotypic and genetic changes associated with cellular activation.
Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies
Published in OncoImmunology, 2022
Ángel Ramírez-Fernández, Óscar Aguilar-Sopeña, Laura Díez-Alonso, Alejandro Segura-Tudela, Carmen Domínguez-Alonso, Pedro Roda-Navarro, Luis Álvarez-Vallina, Belén Blanco
In order to assess if the differences observed in synapse topology might have functional consequences, the early signaling triggered upon J-CAR-T19 and J-STAbT19 interaction with CD19+ Raji cells was studied. As activation controls, J-NT-T cells were stimulated with BLI- or SEE-loaded Raji cells. As negative control, J-NT-T cells were incubated with Raji cells alone. PLCγ1 and ERK1/2 activation was analyzed by Western blot due to their important role in early activation signaling downstream the TCR/CD3. Interestingly, J-STAb-T19 cells showed PLCγ1 and ERK1/2 activation kinetics similar to J-NT-T cells stimulated with SEE or BLI. However, J-CAR-T19 cells showed a more transient signaling compared to J-STAb-T19 cells and control stimulation conditions (Figure 1g,h and Fig. S3).
PKHB1, a thrombospondin-1 peptide mimic, induces anti-tumor effect through immunogenic cell death induction in breast cancer cells
Published in OncoImmunology, 2022
Kenny Misael Calvillo-Rodríguez, Rodolfo Mendoza-Reveles, Luis Gómez-Morales, Ashanti Concepción Uscanga-Palomeque, Philippe Karoyan, Ana Carolina Martínez-Torres, Cristina Rodríguez-Padilla
Here, we assessed for the first time the characteristics of the cell death induced by PKHB1 in breast cancer cells, including the triple negative phenotype, which conserves the principal molecular characteristics of cell death (caspase-independent, calcium-dependent, PLC-dependent, and IP3R and RYR receptor-dependent cell death with the presence of ROS, loss of mitochondrial membrane potential and the intracellular accumulation of Ca2+) reported mainly in leukemic cells.9,11,12,14 We recently reported the overexpression of PLCγ1 and its importance in the cell death induced by PKHB1 in CLL cells,9 but although here we did not assess specially this isoform, it has been demonstrated the the overexpression of PLCγ1 in breast cancer patients is correlated with poor clinical outcome,20 and the overexpression of PLC-β,¹¯²PLC-ε, and PLC-δ has negative outcomes.21 Thus, the involvement of PLC in the mechanism of PKHB1-cell death, might have an advantage in the cancer cells that overexpress these proteins.
Cordycepin exhibits a suppressive effect on T cells through inhibiting TCR signaling cascade in CFA-induced inflammation mice model
Published in Immunopharmacology and Immunotoxicology, 2020
Xiaoli Wang, Deshuang Xi, Jian Mo, Ke Wang, Yu Luo, Erbin Xia, Rong Huang, Shunrong Luo, Jiao Wei, Zhenghua Ren, Hui Pang, Rirong Yang
T cell receptor (TCR) signaling cascade is composed by a series of molecules, such as LCK, ZAP70, LAT, and PLCγ1 [9]. When TCR signaling is stimulated, three downstream signaling pathways, including the nuclear factor of activated T cells (NFAT), the mitogen-activated protein kinase (MAPK) kinase, and the nuclear factor-κB (NF-κB) signaling pathways, could be activated, leading to T cell activation, proliferation, and/or cytokines production [9–11]. When TCR signal is triggered, the SRC family kinase (SFK) members LCK (also known as p56-LCK) is firstly recruited to the TCR-CD3 complex to phosphorylate the immunoreceptor tyrosine-based activation motif (ITAM) of TCR associated CD3ζ-chain residues [9–11]. Elevated CD3ζ phosphorylation is functionally connected to the recruitment of ZAP70 (ζ-chain associated protein kinase of 70 kDa), which is also phosphorylated by LCK [9–11]. Then, activated ZAP70 can induce LAT (linker for activation of T cells) phosphorylation. Phosphorylated LAT recruits adaptors or signaling molecules to form a multiprotein complex named LAT signalosome [9–11]. Phospholipase Cγ1 (PLCγ1) is a key member of LAT signalosome. When PLCγ1 is recruited to LAT signalosome and phosphorylated, it mainly activates NFAT and MAPK pathways for T cell activation and proliferation [9–11].