MAPK signaling and ARTD family members (Homo sapiens)

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The mitogen-activated protein kinase (MAPK) pathway is a series of cytoplasmic phosphorylation events triggered by the binding of mitogens, growth factors, and cytokines to their receptors.

• MAPK signaling effects on ARTD family members*

ERK signaling positively regulates both the expression and activity of PARP1. When MEK, the kinase upstream of ERK in the MAPK cascade, was inhibited in conditioned medium-stimulated endothelial cells, it decreased PARP1 expression. On the other hand, overexpressing p-ERK2 in neurons led to an increase in PARP1 activity.

ERK signaling also influences Tankyrase 1 activity. In 3T3-L1 fibroblasts and adipocytes stimulated by insulin, PDGF, and EGF, ERK phosphorylates Tankyrase 1.

JNK1 has been suggested as a positive regulator of PARP1 activation during H2O2-induced cell death in mouse embryonic fibroblasts (MEFs). In the context of multiple myeloma, JNK2 enhances PARP14 protein levels through an unknown mechanism.

• Positive regulation*

MAPK signaling is positively regulated by PARP1 and Tankyrase 1/2. Under normal conditions, phosphorylation of ERK1/2 (p-ERK1/2) by MEK1/2 (MAPKK) induces conformational changes that activate ERK1/2, leading to the phosphorylation of downstream targets that promote cell growth, survival, and migration.

Perfusing rat hearts with a cytostatic agent increased cardiotoxicity and phosphorylation of ERK, JNK, and p38. Inhibition of PARP1-dependent ADP-ribosylation with BGP-15 significantly reduces MAPK phosphorylation.

PARP1 activation also correlates with JNK and p38 signaling in various cell types, especially in the context of ROS-dependent PARP1 activation and cell death, which depends on JNK and/or p38 signaling.

Although primarily observed in Drosophila melanogaster rather than mammalian cells, Tankyrase 1/2 have been implicated in JNK activation.

• Negative regulation*

In the case of Salmonella infection in human colonic epithelial cells, PARP inhibitor PJ-34 treatment increases ERK phosphorylation, NF-κB signaling, and IL-6 production/secretion, even at early time points.

Inhibition of PARP1 increased ERK activation and reduced cell death in H2O2-induced apoptosis of human WRL-68 cells, while simultaneously lowering p-JNK and p-p38 levels. PARP14 interacts with and likely ADP-ribosylate JNK1, inhibiting its kinase activity and reducing JNK1-dependent apoptosis. Similarly, inhibition of PARP14 with PJ-34 leads to increased JNK1 activity and enhanced cell death.