Microtubule affinity-regulating kinase (MARK)

Microtubule affinity-regulating kinases (MARKs) are a family of four serine/threonine kinases (MARK1, MARK2, MARK3, and MARK4) that play a critical role in regulating microtubule stability by phosphorylating microtubule-associated proteins (MAPs), such as tau, MAP2, and MAP4 (UniProt, 2024). This phosphorylation occurs at specific KXGS motifs, causing the MAPs to detach from microtubules and leading to microtubule destabilization and remodeling (Matenia and Mandelkow, 2009). Beyond microtubule dynamics, MARKs are essential for establishing and maintaining cell polarity and facilitating intracellular transport (PubMed, 2023). In pathological contexts, MARK-mediated hyperphosphorylation of tau is recognized as a primary and early event in the development of neurofibrillary tangles in Alzheimer's disease (NIH, 2022). Additionally, MARK isoforms, particularly MARK4, are frequently overexpressed in various malignancies, promoting tumor cell migration, invasion, and proliferation (PubMed, 2021). Current therapeutic research is focused on developing selective small-molecule MARK inhibitors to prevent tau-mediated neurodegeneration and to serve as potential anti-cancer agents (StatPearls, 2023).

Other names

MAP/microtubule affinity-regulating kinasePar-1ELKL motif kinaseEMKSerine/threonine-protein kinase MARK

Inhibition of the catalytic activity of MARK to prevent the phosphorylation of microtubule-associated proteins, particularly tau protein, thereby stabilizing microtubules and reducing pathological protein aggregation.