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.

Keywords: GPCRs; MAPK; atypical signaling; kinases; mechanisms; p38; vascular disease.

Figure 1

Mechanisms of mitogen-activated protein kinase (MAPK) p38 activation: (A) Inflammatory ligands and environmental stress trigger the activation of a three-tiered kinase cascade. Environmental or inflammatory ligands induce the activation of MAP3Ks through a complex array of different mechanisms. MAP3Ks then activate the critical MAP2Ks, MKK3, MKK6, or (less commonly) MKK4. These MAP2Ks can then differentially activate the four isoforms of p38 (α, β, γ, and δ). (B) The known mechanisms for atypical p38 signaling are (i) GPCR stimulation triggers G-protein dependent c-Src phospho-activation of the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-2 (NEDD4-2). GPCRs recruit and are ubiquitinated by NEDD4-2. K63 ubiquitin chains recruit the ubiquitin-binding adaptor protein TAK1-binding protein 2 (TAB2). In turn, TAB2 then recruits TAB1, which binds and induces autophosphorylation of p38α. (ii) Oxidative stress triggers TGFβ activation, which drives TAB1 and p38 activation, although the exact mechanism is unclear. (iii) Ischemia or hypoxia events drive activation of AMP-activated protein kinase (AMPK), which in turn promotes the formation of the TAB1-p38α complex and p38α autophosphorylation. This process is negatively regulated by the heat shock protein 90 (HSP90)-Cdc37 complex. (C) T-cell receptor (TCR) ligation to major histocompatibility complex (MHC) drives intracellular activation of the src-family zeta-chain-associated protein kinase 70 (Zap70). Zap70 phosphorylates p38 at tyrosine 323, enabling autophosphorylation of p38α, or β.