MAPK14

Detailed Information

The MAPK14 (Mitogen-Activated Protein Kinase 14) gene is located at chromosomal region 6p21.3 and encodes the p38α protein, a key member of the mitogen-activated protein kinase (MAPK) family. As an integrative node within cellular signal transduction networks, it plays a crucial role in regulating cellular proliferation, differentiation, transcription, and development. The gene undergoes alternative splicing to produce at least four transcript variants. Variant 1 (NM_001315) encodes isoform 1, consisting of 360 amino acids, while variant 4 (NM_139014) encodes a shorter isoform of 307 amino acids due to internal deletions. These structural differences result in significant functional divergence in kinase activity and substrate specificity.

The MAPK14 protein structure comprises a conserved N-terminal ATP-binding pocket, a central kinase domain (containing the dual phosphorylation motif Thr180/Tyr182 within the activation loop), and a C-terminal auto-inhibitory domain. Its activation follows two primary pathways: the classical pathway, dependent on phosphorylation by upstream MAP2Ks (MKK3/6), and a non-canonical pathway involving TAB1-mediated autophosphorylation, which is especially critical in osmotic stress responses in cardiomyocytes. The MAPK14 substrate network is extensive, including transcription factors (e.g., ATF2, MEF2C, p53), cell cycle regulators (CDC25B, CDC25C), RNA-binding proteins (such as ZFP36, which modulates mRNA stability), and cytoskeletal components. This multi-target profile underscores its role as a central mediator linking environmental stimuli to cellular responses.

Figure 1. MAPK signalling in pathogenesis. (Fang JY, et al., 2005)

Biological Functions and Regulatory Mechanisms

MAPK14 plays a pivotal role in stress responses and immune regulation. Upon exposure to environmental stressors such as UV radiation or osmotic pressure changes, or in response to pro-inflammatory cytokines like TNF-α and IL-1β, MAPK14 is rapidly activated. It phosphorylates downstream effectors to orchestrate a broad range of physiological responses. In inflammatory signaling, for instance, MAPK14 promotes the shedding of the TGF-α ectodomain by phosphorylating the metalloprotease ADAM17, thereby enhancing EGFR pathway activation. Under oxidative stress, MAPK14 phosphorylates S100A9 at Thr113, enhancing its interaction with TLR4 and promoting macrophage recruitment to inflamed sites.

Recent findings by Cheng Haibo's group in 2025 revealed a novel role of MAPK14 in remodeling the tumor immune microenvironment. In colorectal cancer models, the natural compound lobeline was shown to bind directly to the Lys53 residue of MAPK14, preventing its nuclear translocation. This inhibition led to reduced phosphorylation of p53 at Ser15 and subsequently activated the expression of SLURP1 (Secreted LY6/PLAUR Domain Containing 1), an immunomodulatory protein. SLURP1 enhances the polarization of tumor-associated macrophages (TAMs) toward the anti-tumorigenic M1 phenotype while suppressing the pro-tumorigenic M2 phenotype. This immune reprogramming significantly improved the efficacy of anti-PD-1 antibody therapy, offering a new strategy for combination immunotherapy.

At the epigenetic level, MAPK14 modulates gene expression via two mechanisms: first, it phosphorylates histone H3 at Ser10 (H3S10ph), increasing chromatin accessibility and promoting NF-κB recruitment to inflammatory gene promoters (e.g., IL6, IL8); second, it forms a glucose-sensing complex with O-GlcNAc transferase (OGT), enhancing OGT-mediated modification of neurofilament H under low-glucose conditions. This post-translational modification competes with phosphorylation to regulate cytoskeletal dynamics.

MAPK14 also plays a key role in mitochondrial function. Under UV-B exposure, MAPK14 activates the NLRP1 inflammasome via MAP3K20/ZAK-mediated phosphorylation, inducing pyroptosis, a process implicated in skin carcinogenesis.

Disease Associations and Molecular Mechanisms

Aberrant MAPK14 signaling is implicated in a variety of diseases, particularly cancers and inflammatory conditions:

Gastric Cancer and Tumor-Suppressive Role of circMAPK14

In 2024, studies revealed significantly lower expression of the circular RNA circMAPK14 (hsa_circ_24603) in gastric cancer tissues compared to adjacent normal tissues. Its expression was inversely correlated with tumor progression. Mechanistically, circMAPK14 acts as a molecular sponge for miR-330-5p, thereby relieving its repression of MAPK14 mRNA. When circMAPK14 expression is downregulated, miR-330-5p is upregulated, inhibiting MAPK14 translation and triggering two key outcomes: decreased MAPK14 phosphorylation reduces p53 activation, and pro-apoptotic genes (Bax, Puma, Noxa) are downregulated. Functional assays in SGC7901 cells showed enhanced proliferation, increased migration, and resistance to TBH-induced apoptosis upon circMAPK14 knockdown. Additionally, circMAPK14 deficiency promoted epithelial-mesenchymal transition (EMT), increasing lymph node metastasis risk.

Placental Development Disorders

Knockout studies in mice have demonstrated that MAPK14 is essential for vascular development in the labyrinth layer of the placenta during mid-gestation. Its absence leads to defective embryonic vasculature, reduced exchange surface area, intrauterine growth restriction (IUGR), and embryonic lethality. This effect is linked to impaired expression of erythropoietin (EPO), where MAPK14 phosphorylates the transcription factor C/EBPβ at the EPO enhancer to regulate its activity.

Immune Evasion by Pathogens

Mycobacterium tuberculosis employs its virulence factor EsxA to phosphorylate MAPK14 within T cells, suppressing IFN-γ production within 15 minutes of infection and weakening host immunity. Clinical isolates show a correlation between EsxA phosphorylation efficiency and pathogenicity, suggesting MAPK14 as a potential therapeutic target in tuberculosis.

Table: Roles and Clinical Relevance of MAPK14 in Human Diseases

Therapeutic Strategies and Future Perspectives

MAPK14-targeted therapies are evolving in a disease-specific manner:

Inflammatory Diseases: Traditional p38 inhibitors like SB203580 act via ATP-binding site inhibition. While they reduce inflammatory markers in clinical trials for rheumatoid arthritis, their long-term efficacy is limited by compensatory pathway activation. Next-generation allosteric inhibitors (e.g., Skepinone-L) target the kinase's C-terminal regulatory domain to enhance isoform selectivity and reduce toxicity.

Cancer Therapy: Natural compounds such as lobeline offer a novel mechanism for MAPK14 inhibition. Cheng Haibo's team showed that lobeline binds MAPK14 at Lys53, disrupting its interaction with importin-α and preventing nuclear translocation. This shift in subcellular localization alters the p53 phosphorylation pattern from Ser15 to Ser46, enhancing transcription of the pro-apoptotic gene PUMA. In colorectal cancer organoid models, lobeline (50 μM) enhanced PD-1 antibody efficacy by 3.2-fold. This synergy arises from MAPK14 inhibition–induced effects, including increased CD8+ T cell infiltration, M1 macrophage polarization, and PD-L1 downregulation.

circRNA Replacement Therapy: In gastric cancer, restoration of circMAPK14 using liposome-encapsulated mimetics successfully increased MAPK14 levels and reduced tumor volume by 58% in animal models. This approach minimizes systemic toxicity associated with gene overexpression, enabling precise local intervention.

The principal challenge ahead lies in balancing MAPK14's dual role: tumor suppression in early stages versus promotion of inflammatory mediators in established tumor microenvironments. Potential solutions include microenvironment-responsive nanocarriers (e.g., pH-sensitive liposomes) and targeting tissue-specific splice variants such as EXIP, which has distinct functions in apoptosis initiation.

As a central hub linking stress responses to immune regulation, MAPK14 remains a promising target across oncology, inflammatory, and infectious diseases. Continued dissection of its multifaceted roles will pave the way for next-generation precision therapies.