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Mitogen-activated protein kinase (MAPK) p38 is a central regulator of intracellular signaling, driving physiological and pathological pathways. With over 150 downstream targets, it is predicted that spatial positioning and the availability of cofactors and substrates determine kinase signaling specificity. The subcellular localization of classical mitogen-activated kinase kinase 3/6 (MKK3/6) dependent p38 is highly dynamic to facilitate the selective activation of spatially restricted substrates displaying rapid nuclear translocation. In addition to classical MKK3/6-dependent p38 activation, the adaptor protein TAB1 can selectively bind to p38, inducing p38 autophosphorylation in a pathway termed atypical p38 activation. Our recent studies have linked atypical p38 activity to a wide range of pathological signaling responses, including vascular inflammation and ischemic damage. Through the development of genetically encoded fluorescence resonance energy transfer (FRET) biosensors to track p38 activity with subcellular resolution. Establishing a novel spatial bias of atypical p38 signaling that we predicted is essential for the regulation of vascular diseases. In our current studies, we explore the role of atypical p38 signaling in retinal development and diabetic retinopathy. Using a Tab1KI mouse defective for atypical p38 activation, we show that this spatially selective signaling is critical for vascular dysregulation during oxygen-induced retinopathy (OIR), a model of proliferative diabetic retinopathy. Wildtype postnatal day 7 C57BL6 mice (P7), were exposed to 75% O2 for five days, before returning to normoxic conditions. This triggered robust vaso-obliteration followed by the hyperproliferative response with excessive vascular growth, vascular tufting, and edema. Contrary to this the Tab1KI mice are protected from vascular damage. We show a significant reduction in vascular obliteration, suppressed vascular regrowth, and reduced inflammatory signaling. These data are support by studies using primary human retinal endothelial cells where we show that atypical p38 signaling is essential for proinflammatory responses. The data presented provide the first examination of the atypical p38 activity in the retina and demonstrate a novel mechanism to regulate vascular damage. These data represent an intriguing target for regulating diabetic retinopathy and retinopathy of prematurity.
Grimsey et al. (Fri,) studied this question.