p38 delta: Small Molecules and Peptides

The p38 Mitogen-activated Protein Kinases (MAPKs) are a family of four related Ser/Thr kinases activated by proinflammatory cytokines and environmental stresses. All four p38 family members, alpha, beta, gamma, and delta, are phosphorylated by MKK3 and/or MKK6 at dual Thr and Tyr positions within the phosphoacceptor sequence Thr-Gly-Tyr. Once activated, p38 phosphorylates a number of targets, including the nuclear transcription factors ATF2 and Max.

The most frequently analyzed family member, p38 alpha, also known as SAPK2a and MAPK14, was initially purified as a kinase critical to the signaling cascade linking IL-1 to MAPKAPK-2 and the small heat shock protein HSP27. Ubiquitously expressed, p38 alpha is dually phosphorylated by MKK3 and MKK6 at Thr180 and Tyr182. Once activated, p38 alpha phosphorylates a number of targets, including the cytoplasmic kinases MNK 4 and PRAK5 and the nuclear transcription factors ATF2 1 and STAT1. Several promising compounds that inhibit p38 alpha are being investigated as potential therapies for arthritic and inflammatory diseases.