Microtubule affinity-regulating kinase 2 and 3 (MARK2/3)

Microtubule affinity-regulating kinase 2 and 3 (MARK2/3) are members of the Par-1 family of serine/threonine kinases that play essential roles in establishing cell polarity and regulating microtubule dynamics [7, 9]. They function by phosphorylating microtubule-associated proteins (MAPs), such as tau, MAP2, and MAP4, which causes them to detach from microtubules and increases microtubule instability [5, 10]. In the context of neurodegenerative diseases like Alzheimer's, MARK2/3-mediated hyperphosphorylation of tau at the Ser262 residue is a critical early step in the formation of neurofibrillary tangles [6, 18, 20]. Recent research has also identified MARK2/3 as key regulators of the Hippo signaling pathway in various cancers, where they promote the activity of the YAP/TAZ oncogenes by inhibiting the tumor-suppressive LATS1/2 kinases through phosphorylation of NF2 and YAP/TAZ [1, 2, 25]. Consequently, MARK2/3 are emerging as promising therapeutic targets for both oncology and neurodegeneration [1, 31]. Small molecule inhibitors, including the ALK inhibitor brigatinib and novel compounds like PCC0208017, have shown potential in modulating MARK2/3 activity to suppress tumor growth and tau pathology [29, 31]. However, therapeutic development must account for the kinases' roles in normal neuronal function and metabolism, as knockout models suggest potential risks of growth retardation and fertility issues [18, 20]. Targeting these kinases offers a unique strategy to restore Hippo pathway-mediated tumor suppression in YAP/TAZ-dysregulated carcinomas and sarcomas [2, 32].

Other names

MAP/microtubule affinity-regulating kinase 2MAP/microtubule affinity-regulating kinase 3ELKL motif kinase 1 (EMK1)ELKL motif kinase 2 (EMK2)Partitioning defective 1 homolog b (PAR-1b)Partitioning defective 1 homolog a (PAR-1a)Serine/threonine-protein kinase MARK2Serine/threonine-protein kinase MARK3KP78

Inhibition of MARK2/3 kinase activity, which leads to the reactivation of the Hippo tumor suppressive pathway by reducing YAP/TAZ function in cancer, and the reduction of tau hyperphosphorylation in neurodegenerative contexts.