Atypical p38 Signaling, Activation, and Implications for Disease

Abstract

The mitogen-activated protein kinase (MAPK) p38 is an essential family of kinases, regulating responses to environmental stress and inflammation. There is an ever-increasing plethora of physiological and pathophysiological conditions attributed to p38 activity, ranging from cell division and embryonic development to the control of a multitude of diseases including retinal, cardiovascular, and neurodegenerative diseases, diabetes, and cancer. Despite the decades of intense investigation, a viable therapeutic approach to disrupt p38 signaling remains elusive. A growing body of evidence supports the pathological significance of an understudied atypical p38 signaling pathway. Atypical p38 signaling is driven by a direct interaction between the adaptor protein TAB1 and p38α, driving p38 autophosphorylation independent from the classical MKK3 and MKK6 pathways. Unlike the classical MKK3/6 signaling pathway, atypical signaling is selective for just p38α, and at present has only been characterized during pathophysiological stimulation. Recent studies have linked atypical signaling to dermal and vascular inflammation, myocardial ischemia, cancer metastasis, diabetes, complications during pregnancy, and bacterial and viral infections. Additional studies are required to fully understand how, when, where, and why atypical p38 signaling is induced. Furthermore, the development of selective TAB1-p38 inhibitors represents an exciting new opportunity to selectively inhibit pathological p38 signaling in a wide array of diseases.

Mettl3 promotes oxLDL‐mediated inflammation through activating STAT1 signaling

“…Considering that inflammatory response is usually triggered by mitogen‐activated protein kinase (MAPK) signaling, such as p38 and Jun‐NH(2)‐terminal kinase (JNK), p65 nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling, and Janus kinase (JAK)‐signal transducer and activator of transcription 1/3(STAT1/3) signaling, 22 , 23 , 24 , 25 , 26 we further explored whether Mettl3 promoting oxLDL‐induced inflammatory response in macrophages is associated with these signaling pathways. As shown in Figure 3A , oxLDL stimulation significantly increased the protein expressions of phosphorylated p38 (p‐p38), p‐JNK1/2, p‐p65, p‐STAT1, and p‐STAT3, while Mettl3 knockdown obviously suppressed the upregulation of total STAT1 and p‐STAT1 protein expressions.…”

Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice

“…JNK and p38 are well-studied signaling cascades that are essential for vital cellular activities [4,5]. The activation of MAPK JNK and p38 are mediated by several members of the evolutionary conserved upstream mitogen-activated protein kinases kinase (MAP2K) family [6][7][8]. Such diversity in the repertoire of upstream activators might, in turn, define the specificity of the stimuli-induced pathway activation.…”

From DNA Damage to Cancer Progression: Potential Effects of Cytolethal Distending Toxin

“…The downstream pathway of RhoA diverges into p38 MAPK and Rho-associated kinase (ROCK) signaling. Aside from a plethora of reports concerning the proinflammatory effect of p38 MAPK (90)(91)(92), it has also been reported that sustained p38 MAPK is vital for cell survival under genotoxic stress (13,93,94). In parallel, ROCK signaling manipulates the stress fiber formation and cellular contractility (95).…”