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 P38 Signaling

The p38 mitogen-activated protein (MAP) kinase family contains four members: p38 (p38α, p38alpha, CSBP, RK, SAPK2a); p38β (p38beta, SAPK2b); p38γ (p38gamma, ERK6, SAPK3) and p38δ (p38delta, SAPK4). P38 and p38beta are ubiquitous. P38gamma is found predominately in muscle and p38delta is expressed in lung, pancreas, kidney, testis, and small intestine. P38 MAP-kinases all contain the same duel phosphorylation motif, thr-gly-tyr (TGY). The p38 MAP-kinases are activated coordinately by physical-chemical stresses such as: high osmolarity; uv light; or hydrogen peroxide induced oxidative stress; pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and TGFbeta (TGFβ) and death receptors (Fas). These stress signals activate a range of MAP3K level kinases such as the RHO-GTPase (Cdc42 and Rac1) downstream effector, p21/Cdc42/Rac1-activated kinase 1 (PAK1); transforming growth factor beta-activated kinase-1 (TAK1) and mitogen-activated protein kinase kinase kinase (ASK1), which in turn activate various MAP2Kinases, the MKKs. P38 alpha, gamma and delta MAPkinase are activated by both MKK3 and MKK6 (SKK3). In addition, p38 is activated along with JNKs by MKK4. P38beta is activated only by MKK6 (SKK3).

The downstream targets of the p38 MAPkinases include a wide array of cytoplasmic and nuclear factors. Key targets include the 90-kDa ribosomal S6 kinase (pp90rsk) (RSK) family: RSK1, RSK2, MNK1/2 and MSK1/2 and nuclear translation factors such as Elk-1, ATF2, STAT3 and CREB. These factors represent only a small number of the p38 substrates. Cellular response to stress activation depends upon the activity of each specific p38 isoform and cell context.