Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

• Keywords
• ERK, Hippo, MAPK, MST, PI3K, YAP, apoptosis, cancer, caspase, inhibitors, natural compounds, therapy,
• MeSH
• Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors   metabolism   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Humans MeSH
• Neoplasms drug therapy   metabolism   MeSH
• Protein Serine-Threonine Kinases antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Hippo Signaling Pathway MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Extracellular Signal-Regulated MAP Kinases MeSH
• Protein Kinase Inhibitors MeSH
• Protein Serine-Threonine Kinases MeSH
• Antineoplastic Agents MeSH

The discrete activation of individual caspases is essential during T-cell development, activation, and apoptosis. Humans carrying nonfunctional caspase-8 and caspase-8 conditional knockout mice exhibit several defects in the progression of naive CD4⁺ T cells to the effector stage. MST1, a key kinase of the Hippo signaling pathway, is often presented as a substrate of caspases, and its cleavage by caspases potentiates its activity. Several studies have focused on the involvement of MST1 in caspase activation and also reported several defects in the immune system function caused by MST1 deficiency. Here, we show the rapid activation of the MEK-ERK-MST1 axis together with the cleavage and activation of caspase-3, -6, -7, -8, and -9 after PI3K signaling blockade by the selective inhibitor GDC-0941 in Jurkat T cells. We determined the phosphorylation pattern of MST1 using a phosphoproteomic approach and identified two amino acid residues phosphorylated in an ERK-dependent manner after GDC-0941 treatment together with a novel phosphorylation site at S21 residue, which was extensively phosphorylated in an ERK-independent manner during PI3K signaling blockade. Using caspase inhibitors and the inhibition of MST1 expression using siRNA, we identified an exclusive role of the MEK-ERK-MST1 axis in the activation of initiator caspase-8, which in turn activates executive caspase-3/-7 that finally potentiate MST1 proteolytic cleavage. This mechanism forms a positive feed-back loop that amplifies the activation of MST1 together with apoptotic response in Jurkat T cells during PI3K inhibition. Altogether, we propose a novel MEK-ERK-MST1-CASP8-CASP3/7 apoptotic pathway in Jurkat T cells and believe that the regulation of this pathway can open novel possibilities in systemic and cancer therapies.

• Keywords
• AKT, ERK, Hippo/MST1, MEK, PI3K, apoptosis, caspase,
• MeSH
• Enzyme Activation drug effects   MeSH
• Apoptosis drug effects   MeSH
• Models, Biological MeSH
• Down-Regulation drug effects   MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Phosphorylation drug effects   MeSH
• Phosphothreonine metabolism   MeSH
• Hepatocyte Growth Factor chemistry   metabolism   MeSH
• Indazoles pharmacology   MeSH
• Phosphoinositide-3 Kinase Inhibitors MeSH
• Caspase Inhibitors pharmacology   MeSH
• Jurkat Cells MeSH
• Caspases metabolism   MeSH
• Humans MeSH
• MAP Kinase Signaling System drug effects   MeSH
• Mitogen-Activated Protein Kinase Kinases metabolism   MeSH
• Piperazines pharmacology   MeSH
• Proteolysis drug effects   MeSH
• Proto-Oncogene Proteins chemistry   metabolism   MeSH
• Amino Acid Sequence MeSH
• Sulfonamides pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine MeSH Browser
• Phosphothreonine MeSH
• Hepatocyte Growth Factor MeSH
• Indazoles MeSH
• Phosphoinositide-3 Kinase Inhibitors MeSH
• Caspase Inhibitors MeSH
• Caspases MeSH
• macrophage stimulating protein MeSH Browser
• Mitogen-Activated Protein Kinase Kinases MeSH
• Piperazines MeSH
• Proto-Oncogene Proteins MeSH
• SCH772984 MeSH Browser
• Sulfonamides MeSH