UCSD Molecule Pages

In mammals, there are four p38 protein kinases: p38α, p38β, p38γ and p38δ. p38β was identified in 1996 as a closely related protein kinase of p38α, sharing 74% sequence identity and the Thr-Gly-Tyr dual phosphorylation motif characteristic of all p38 MAPKs. p38β is widely distributed in cells and tissues, but less so than p38α; p38β is particularly abundant in endothelial cells. p38β is activated in vivo by dual phosphorylation at Thr180 and Tyr182 by the MAP2K, MKK3 and MKK6 in response to a multitude of stimuli including environmental stressors, cytokines and growth factors. p38β can be dephosphorylated on both its Thr and Tyr residues by Dual-Specificity Phosphatases. p38β, like p38α, is targeted by a class of pyridinyl imidazole drugs that do not target the other two p38 MAPKs. These compounds were invaluable in discovering functions regulated by p38α and p38β. However, they do not permit to distinguish functions mediated by p38β from those regulated by p38α. This distinction has been made possible by the use of genetically engineered mice. p38β-deficient mice are not embryonic lethal such as those lacking p38α. However ectopic expression of p38β can rescue the lethality of p38α-deficiency. This suggests that p38α is the “dominant” form but that functional redundancy exists between the two related protein kinase. p38β has been shown to play specific roles in gene expression, regulation of cell death, cell differentiation and neuropathic pain. However, p38β is not involved in transducing pro-inflammatory signals, myogenesis or cell motility, when p38α is present.