Tau is a neuronal microtubule-binding protein that forms characteristic neurofibrillary tangles (NFT), upon hyperphosphorylation, hyperacetylation, and aggregation, which are hallmark biomarkers for Alzheimer’s disease (AD). The pathophysiological conversion of tau still remains unclear, but the regulation and synergy of tau’s post-translational modifications (PTMs) by certain enzymes can be monitored. This study investigates the interactions between two enzymes involved in regulating tau’s PTMs: the microtubule affinity-regulating kinase (MARK2) and the acetyltransferase CREB-binding protein (CBP). We performed a series of biochemical analyses, which uncovered that CBP-mediated acetylation was increased in the absence of MARK2, indicating a possible negative feedback loop, in which MARK2 is phosphorylating and thereby inhibiting CBP. Further investigation of the protein-protein interactions revealed increased acetylation of an inactive MARK2 mutant compared to wild-type MARK2 in the presence of CBP. This finding supports the idea that active MARK2 may be involved in decreasing CBP-mediated acetylation. Although the exact mechanism of this interaction and its role in tau dysfunction have yet to be determined, we have uncovered a new signaling pathway in which two enzymes may regulate each other.