How?

When?

Why?

The Regulation of Pathological Signaling

University of Georgia, Athens

College of Pharmacy

Department of Pharmaceutical and Biomedical Sciences

Activation Of Kinases

Classical and Atypical p38

Kinases regulate the phosphorylation of substrate proteins dynamically tuning activation and interactions.
Mitogen-activated protein kinases (MAPK) are activated inside cells to control a wide range of physiological functions.

The classical signaling uses MKK3/6 to activate p38, this pathway regulates all the “good” physiological signaling. But when overactive can cause many diseases

Whereas, atypical p38 uses a distinctly different pathway. Where the Adaptor protein TAB1 binds to p38 activating disease-causing signaling.

G Protein-Coupled Receptor (GPCR) Atypical Inflammatory Signaling

Where kinases are in space and time (the spatiotemporal dynamics) impacts vascular inflammation in many diseases. More specifically, we study G protein-coupled receptors (GPCRs) which are expressed throughout the body, playing critical roles in many physiological functions ranging from the control of taste and sight to the regulation of neuronal function and inflammatory responses.  GPCRs are sensors for extracellular stimuli, and as such are activated by a wide array of ligands to induce intracellular signaling cascades, principally through the activation of the heterotrimeric G proteins.

Dysregulation of GPCR expression or activation is a lead cause in the onset and progression of many human diseases including pulmonary diseases; acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), and neurovascular inflammation, diabetes, Alzheimer’s disease, and multiple sclerosis. Consequently, GPCRs represent the largest family of proteins targeted by current FDA-approved drugs. 

Our interests focus on defining how atypical GPCR signaling is dynamically controlled inside each cell.

Pathophysiological Impact

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Atypical p38 at the center of disease.

There is a wide spectrum of triggers and pathologies linked to p38 activity. We predict that atypical p38 is a major contributor to human disease. Defining how, where, and why atypical p38 is activated will reveal fundamental insights into why these diseases occur and identify novel targets for therapeutic intervention. (See our Review, Burton et al 2021, Implications of atypical p38 in health and disease).

Our ongoing studies explore the role of atypical p38 in acute lung injury, blinding diseases including oxygen and diabetic-induced retinopathies, and viral replication.