p38 Mitogen-activated protein kinase-AKT signaling pathway (p38-AKT)

The p38-AKT signaling pathway is a complex intracellular regulatory network involving the p38 mitogen-activated protein kinase (MAPK) and the AKT (Protein Kinase B) serine/threonine kinase families [1]. While p38 is primarily associated with stress responses and cytokine production, AKT is a central mediator of growth factor-induced survival and metabolism [2]. These two pathways frequently exhibit crosstalk, where p38 can influence AKT activation through downstream effectors like MK2, or AKT can modulate p38 activity to balance pro-survival and pro-apoptotic signals [3]. Dysregulation of the p38-AKT axis is a common feature in various cancers, where it contributes to tumor growth, metastasis, and resistance to therapy [4]. It also plays a significant role in chronic inflammatory diseases by regulating the expression of pro-inflammatory mediators [5]. Therapeutic targeting of this pathway involves small-molecule inhibitors directed at specific components, such as the AKT inhibitor capivasertib or p38 inhibitors like losmapimod [6]. However, because these kinases are involved in numerous homeostatic processes, pharmacological intervention often faces challenges related to systemic toxicity and complex feedback mechanisms [7]. As a result, this pathway is often studied as a systems-level signaling axis rather than a single discrete therapeutic target [1]. Sources: [1] UniProt (P47811, P31749); [2] PubMed (25613364); [3] PubMed (15105415); [4] PubMed (21810915); [5] NIH/StatPearls (MAPK Signaling); [6] FDA Drug Labels (Truqap); [7] PubMed (19454141).

Other names

p38/AKT axisp38 MAPK-AKT signalingStress-activated protein kinase p38 and Protein kinase B pathwayp38-PKB signaling

The pathway is modulated by small-molecule inhibitors that target its constituent kinases; p38 inhibitors block the phosphorylation of downstream effectors like MK2 to suppress pro-inflammatory cytokine production, while AKT inhibitors prevent the phosphorylation of substrates such as GSK3β and mTORC1 components to inhibit cell growth and survival [1, 2].