Research Progress of Microtubule Affinity-regulating Kinase 4 as Drug Target

Microtubule affinity-regulating kinase 4 (MARK4) is a Ser/Thr protein kinase, best known for its role in phosphorylating microtubule associated proteins, causing their detachment from microtubules thereby increasing microtubule dynamics and facilitating cell shape alterations, cell division, cell cycle control, regulating cell cycle, etc. The MARK4 gene encodes two alternatively spliced isoforms, L and S that differ in their C-terminal region. These isoforms are differentially regulated in human tissues including central nervous system. The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation and the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas. MARK4 exhibits are multi domain structure comprised of an N-terminal header, a catalytic kinase domain, a linker, UBA domain, spacer, and a kinase-associated domain at the C-terminal end. Over-expression of MARK4 is associated with the onset of neurodegenerative diseases such as Alzheimer's disease, metabolism disorders and cancer. Therefore, MARK4 is being considered as a most suitable drug target for cancer, Alzheimer's disease and other neurodegenerative diseases and its structural features are employed in the development of new therapeutic molecules. In this paper, the structure and biological functions of MARK4 and the related diseases mediated by MARK4 were reviewed, and the research progress of MARK4 inhibitors was summarized.