Multifaceted role of zipper-interacting protein kinase beyond cell death: Implication of ZIPK dysregulation in neuronal and vascular injuries

Zipper-interacting protein kinase (ZIPK) belongs to the death-associated protein kinase (DAPK) family and is a serine/threonine kinase. ZIPK is ubiquitously expressed in different types of tissues and cells. ZIPK is involved in many cellular functions, including cell death, smooth muscle contraction, transcriptional regulation, inflammatory signaling and the regulation of angiogenesis. The dysregulation of ZIPK has been shown to be involved in multiple diseases, including cancer, neurological diseases such as stroke, and cardiovascular diseases such as hypertension. The molecular mechanisms by which ZIPK inhibits the development of cancer have been well studied, but less is known about how ZIPK dysregulation is involved in vascular and neurological diseases. In this review, we summarize the current knowledge about the cellular processes in which ZIPK is involved and the pathological relevance of ZIPK dysregulation in diseases, with a focus on the role of ZIPK in vascular and neuronal functions. The molecular mechanisms by which ZIPK dysregulation contributes to cancer and vascular and neuronal diseases are discussed. We also review recent advances in the development of ZIPK modulators and their potential in treating vascular damage and neurological disorders. Multiple findings support that ZIPK has important functions in regulating vascular homeostasis and serves as a novel therapeutic target for alleviating neurological diseases.