MAPK3 (ERK1) is a serine/threonine kinase that functions as an essential component of the MAP kinase signal transduction pathway, working alongside MAPK1/ERK2 in the MAPK/ERK cascade 1. The protein phosphorylates thousands of substrates, with studies identifying 4666 ERK-dependent phosphosites on 2123 proteins, substantially expanding our understanding of ERK-dependent signaling complexity 1. MAPK3 regulates diverse cellular processes including cell growth, survival, differentiation, and apoptosis through phosphorylation of transcription factors, cytoskeletal elements, and signaling molecules 1. In disease contexts, MAPK3 plays critical roles in cancer progression, with elevated MAPK3 levels promoting ULK1 degradation, attenuating mitophagy, and enhancing breast cancer bone metastasis 2. The kinase also contributes to cardiovascular disease, where its upregulation is associated with atherosclerosis development 3. MAPK3 expression is negatively regulated by KLF17 in embryonic stem cells, where its repression is essential for maintaining naive pluripotency 4. Clinical significance includes its potential as a therapeutic target, with MEK inhibitors like trametinib showing promise in reducing bone metastasis by restoring ULK1 levels 2, and various natural compounds demonstrating anti-disease effects through MAPK3 modulation 56.