Atypical P38 Signaling, Activation, and Implications for Disease

International Journal of Molecular Sciences

Review Atypical p38 Signaling, Activation, and Implications for Disease

Jeremy C. Burton , William Antoniades †, Jennifer Okalova †, Morgan M. Roos † and Neil J. Grimsey *

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA; [email protected] (J.C.B.); [email protected] (W.A.); [email protected] (J.O.); [email protected] (M.M.R.) * Correspondence: [email protected] † These authors contributed equally.

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 Citation: Burton, J.C.; Antoniades, to fully understand how, when, where, and why atypical p38 signaling is induced. Furthermore, the W.; Okalova, J.; Roos, M.M.; Grimsey, development of selective TAB1-p38 inhibitors represents an exciting new opportunity to selectively N.J. Atypical p38 Signaling, Activation, and Implications for inhibit pathological p38 signaling in a wide array of diseases. Disease. Int. J. Mol. Sci. 2021, 22, 4183. https://doi.org/10.3390/ Keywords: MAPK; p38; atypical signaling; vascular disease; GPCRs; kinases; mechanisms ijms22084183

Academic Editors: Cristina Banﬁ and Alessandro Cannavo 1. Introduction The p38 mitogen-activated protein kinase (MAPK) family are critical cellular signaling Received: 28 February 2021 regulators that drive many physiological and pathophysiological pathways. Therefore, it is Accepted: 13 April 2021 not surprising that since their discovery in 1994 [1], over 45,000 research articles and reviews Published: 17 April 2021 have been published describing the mechanism of p38 activation and the role of p38 during development and disease progression. The broader MAPK family includes c-Jun activated Publisher’s Note: MDPI stays neutral Kinase (JNK), extracellular signal-related kinase 1 and 2 (ERK1/2), and protein kinase with regard to jurisdictional claims in B, also known as AKT kinase (AKT), all of which are critical in regulating a multitude published maps and institutional afﬁl- of cellular processes from cell division to cell death and everything in between. Cellular iations. stimuli/stress induces the activation of MAPKs, including hormones, growth factors, and cytokines, as well as environmental stressors such as osmotic shock, UV radiation, and ischemic injury [2]. As such, p38 MAPKs have been the subject of intense study to generate clinically effective therapeutics. Despite ongoing clinical trials for many diseases, Copyright: © 2021 by the authors. including ischemic cardiac damage, COPD, multiple cancers, various neuropathies, and Licensee MDPI, Basel, Switzerland. ARDS/COVID-19, only one non-selective p38 inhibitor (pirfe