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. 2021 Mar 15;9:626095. doi: 10.3389/fcell.2021.626095

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Copyright © 2021 Rudd.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Proximal signaling complexes and downstream responses initiated by the CD4/CD8-p56^lck complexes. Model outlining CD4/CD8-p56^lck initiation of the protein-tyrosine activation cascade. CD4/CD8-p56^lck phosphorylation of TCR ITAMs leads to the recruitment and activation of ZAP-70 followed by its phosphorylation and formation of the LAT signalosome. pLAT recruits several SH2-domain-containing proteins, including phospholipase Cγ-1 (PLCγ1) growth factor receptor-bound protein 2 (GRB2) and GRB2-related adaptor protein (GADS). Through its constitutive association with GADS, SLP-76 constitutively associates with LAT. Associated IL-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) phospho-activate PLCγ1 resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 3,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP₃ production leads to increases of intracellular free Ca²⁺ concentration, whereas DAG can activate both protein kinase C- (PKC-θ) and RAS guanyl nucleotide-releasing protein (RASGRP). IP₃ generated from PIP₂ binds to the Ca²⁺⁻permeable ion channel receptors (IP3R) in the endoplasmic reticulum (ER) releasing Ca²⁺ from within ER stores to the cytoplasm. The ER senses intracellular Ca²⁺ levels through stromal interaction molecule (STIM). Depletion of intracellular Ca²⁺ triggers an Ca²⁺influx from Orai1 type plasma membrane calcium-release activated calcium (CRAC) channel. Increased intracellular Ca²⁺ activates a protein phosphatase, calcineurin, that dephosphorylates the nuclear factor of activated T cells (NFAT) for its nuclear translocation. pLAT also recruits the SH2 domain of GRB2 and GRB2-associated RAS guanosine nucleotide-exchange factor (GEF), son-of-sevenless (SOS) to activate p21^RAS. Tyrosine-phosphorylated SLP-76 also associates with the immune cell adaptors ADAP and SKAP1. SKAP1 controls the formation of the Rap1-RapL complex needed for LFA-1 activation. SLP-76 also interacts with RanGAP1 in the nuclear complex for the increased transport of transcription factors NFAT and NFkb into the nucleus.