p38 is a member of a group of kinases known as mitogen-activated protein kinases (MAPK), which are critical for regulation of cell proliferation, inflammation, apoptosis, and cell motility. Various extracellular signals can activate p38 signaling, including stress, inflammation, and growth factors. GPCR signaling through PLC, DAG, and PKC leads to the activation of MAP kinase kinase kinases (MAP3Ks) like MEKK1-4 and MLKs that go on to phosphorylate MAP kinase kinases (MAPKKs). MAPKKs involved in the p38 pathway are MKK3 and MKK6. These then phosphorylate p38, which translocates to the nucleus and activates transcription factors. Receptor tyrosine kinases that bind growth factors recruit SOS to induce Ras signaling, which leads to MKK3 and MKK6 phosphorylation. Inflammatory cytokine receptors activate p38 through ASK1 and MEKK4 (MAP3Ks) phosphorylation, which then triggers the rest of the MAPK phosphorylation sequence. Finally, TCR signaling utilizes ZAP70 instead of MAP3Ks and MAPKKs to activate p38 function.
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