p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα).

p38α MAPK is implicated in diverse cellular functions, from gene expression to programmed cell death through a network of signaling molecules and transcription factors.

MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development.

MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 MAPK which allows kinase activation and accessibility to substrates.

[23][24] Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop.

During cardiomyocyte maturation in new born mouse heart, p38α MAPK activity can regulate myocyte cytokinesis and promote cell cycle exit.

[36][37] Therefore, p38 MAPK is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury.

[40][41][42][43][44][45][46] p38 MAPK can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation.

[53][57][58][59] However, in vivo evidence suggest that chronic activation of p38 MAPK activity triggers restrictive cardiomyopathy with limited hypertrophy,[60] while genetic inactivation p38α MAPK in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload[61][62] or swimming exercise.