Figure 4.

Four p38 subfamilies have been identified: p38-α, -β, -γ, and -δ [96]. MAPK cascade is the main mechanism by which the four p38 isoforms are activated in human cells [97]. Protein kinase activity of p38 is stimulated by oncogenic TAK1 or ASK1 through its downstream mitogen-activated protein kinase kinases, MKK3 and MKK6, under conditions of severe stress and inflammation (under mild stress, the ERK/MAPK pathway is activated) [98]. Activated p38 also interacts with AKT and NF-κB, triggering downstream mTORC1 via the degradation of DEPTOR, or by suppressing the activation of PPARα [95]. These changes promote cell proliferation, inflammation, protein synthesis, and decrease apoptosis, ultimately leading to a hypoxic, acidic, and inflammatory TME.