c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling pathway (JNK/p38 MAPK pathway)

The c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathway is a major signaling cascade of the mitogen-activated protein kinase (MAPK) family. These kinases are **serine/threonine protein kinases** activated primarily by cellular stress, inflammatory cytokines, environmental insults (such as UV irradiation, heat, and osmotic shock), and various growth factors[2][4][7]. JNK comprises isoforms JNK1, JNK2, and JNK3, while p38 MAPK includes p38α, p38β, p38γ, and p38δ. Activation of these kinases occurs via phosphorylation cascades involving MAP kinase kinase kinases (MAP3K), MAP kinase kinases (MAPKK, e.g., MKK4/7 for JNK, MKK3/6 for p38), and the MAPKs themselves[2][4]. Once activated, JNK and p38 regulate numerous cellular processes by phosphorylating transcription factors (such as AP-1, ATF2, CHOP, NF-κB), coregulators, cytoskeletal proteins, and signaling proteins, affecting gene expression, cell cycle, apoptosis, differentiation, immune responses, and stress adaptation[1][2][4][7]. Dysregulation of the JNK and p38 MAPK pathway is implicated in the development and progression of various diseases, notably cancers, inflammatory conditions, neurodegenerative disorders, and treatment resistance in oncology[2][5][8]. While **small molecule inhibitors** (e.g., SP600125, SB203580) and natural products targeting these kinases are subjects of preclinical and limited clinical investigation, challenges in therapeutic application include pathway duality (tumor-suppressive vs. tumor-promoting roles), toxicity from non-specific inhibition, and complexity of signaling crosstalk[5][8]. Importantly, "JNK/p38 MAPK pathway" refers to a **signaling pathway or kinase cascade**, and is **not a single therapeutic target**, protein, or molecular entity. Targeting is generally at the level of individual kinases within these pathways, not the pathway as a whole. **Note:** This designation is not a valid canonical target for drug discovery in the sense of a specific molecular entity. Proper targets would be individual kinases such as "c-Jun N-terminal kinase 1 (JNK1)" or "p38 alpha mitogen-activated protein kinase (MAPK14)". **Key limitation:** "JNK/p38 MAPK pathway" is an over-broad, pathway-level entry—*not a precise target molecule or receptor*. Structured entries for specific kinases (e.g., JNK1, p38α) should be used for high-quality data integration.[4][5][8]

Other names

JNK pathwayp38 MAPK pathwayJNK/SAPK pathwayStress-activated MAPK pathway

- Inhibition of kinase phosphorylation (JNK or p38 MAPK inhibitors prevent pathway activation)[5][8] - Induction or suppression of apoptosis (depending on activation/inhibition context)[5] - Modulation of downstream transcription factors (e.g., AP-1, ATF2, CHOP)[1][2][4] - Enhancement of autophagy, DNA repair, or drug efflux pathways (in chemoresistance)[5]