Evidence for PDZ-Binding Kinase in Lung Disease With an Emphasis on PAH.

Abstract

Originally named T-cell-originated Lymphokine-activated killer protein kinase (TOPK), PDZ-Binding Kinase (PBK) is a serine/threonine kinase that is a member of the family of mitogen-activated protein kinases (MAPKKs), which is overexpressed in lung cancer and interstitial pulmonary fibrosis (IPF). Along these lines, recent work also shows that PBK expression is upregulated in pulmonary arterial hypertension (PAH) in part due to the inappropriate proliferation of pulmonary arterial smooth muscle cells (PASMC), similar to the hyper-proliferative cellular properties seen in both lung cancer and IPF. Genetic knock-out of PBK as well as pharmacologically selective inhibitors of PBK improve PA remodeling and cardiopulmonary function. Further, PBK bound to the Protein Regulator of Cytokinesis 1 (PRC1) induces PRC1 phosphorylation and cytokinesis in PASMC, and thus, it is conjectured that PBK enhances PASMC proliferation via PRC1-mediated cytokinesis, identifying a key mechanism which contributes to the pathologic pulmonary vascular remodeling that occurs in PAH. Towards this end, along with the already published studies showing that PBK is involved in both lung cancer and IPF, PBK-mediated pulmonary vascular remodeling reveals a new signaling pathway in lung vascular disease and a novel mechanism of PASMC proliferation. Exploration of this signaling pathway will advance the utility of identifying novel therapeutic approaches targeting PBK-mediated cytokinesis to reduce pulmonary vascular remodeling (as seen in PAH) and subsequently improve the morbidity and mortality associated with lung vascular disease. Collectively, the literature strongly suggests that PBK is a worthy and viable therapeutic target to pursue in the context of lung disease.