Role of mitogen- and stress-activated kinases in inflammatory arthritis

Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen acti-vated protein （MAP） kinase signaling network, including extracellular signal-regulated kinases （ERK） 1/2 and p38 MAP kinase （MAPK）. Upon docking to mitogen and stress-activated kinases （MSKs）, ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate cAMP response element-binding protein （CREB） at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-infammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, proinflammatory cytokines, and cellular stresses, as well as those induced by LPA.

Stress-activated kinases as therapeutic targets in pancreatic cancer

Pancreatic cancer is a dismal disease with high incidence and poor survival rates.With the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently needed.Protein kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-Jun N-terminal kinases(JNK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(CK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DNA damage,and others.In their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and apoptosis.Dysregulation of the underlying pathways consequently has been identified in various cancer types,including pancreatic cancer.Pharmacological targeting of those pathways has been the field of interest for several years.While success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results.Consequently,targeting of JNK,p38,and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases.However,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.