Microtubule associated proteins regulate the stability of microtubules and control processes such as cell polarity/differentiation, neurite outgrowth, cell division and organelle trafficking. The MARK family of serine/threonine kinases was identified based on their ability to phosphorylate microtubule-associated proteins including tau, MAP2 and MAP4. MARK proteins phosphorylate MAPs within their microtubule binding domains, causing dissociation of MAPs from microtubules and increased microtubule dynamics. In the case of tau, phosphorylation has been hypothesized to contribute to the formation of neurofibrillary tangles observed in Alzheimer's disease. Overexpression of MARK leads to hyperphosphorylation of MAPs, morphological changes and cell death. The tumor suppressor kinase LKB1 phosphorylates MARK and the closely related AMP-kinases within their T-loops, leading to increased activity.MARK3 is an ubiquitously expressed member of the MARK/EMK/Par-1 family that was identified as Cdc25C-associated protein kinase based on its association and ability to phosphorylate Cdc25C. MARK3 substrates include Cdc25C phosphatase, MAPK scaffold kinase suppressor of Ras1, protein-tyrosine phosphatase H1, plakophilin 2, and histone deacetylases. MARK3 phosphorylates Cdc25C on serine 216 in response to DNA damage which allows for the preferential binding of 14-3-3 proteins that control entry into mitosis. MARK3 has also been shown to phosphorylate HDAC7 on one of its 14-3-3 binding sites that effects both the subcellular localization and repressive function of the HDAC.
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