TGF beta Activates Mitogen- and Stress-activated Protein Kinase-1 (MSK1) to Attenuate Cell Death

Heide, L.P. van der; Dinther, M. van; Moustakas, A.; Dijke, P. ten

Transforming growth factor-beta (TGF beta) binding to its receptor leads to intracellular phosphorylation of Smad2 and Smad3, which oligomerize with Smad4. These complexes accumulate in the nucleus and induce gene transcription. Here we describe mitogen-and stress-activated kinase 1 (MSK1) as an antagonist of TGF beta-induced cell death. Induction of MSK1 activity by TGF beta depends on Smad4 and p38 MAPK activation. Knockdown of GADD45, a Smad4-induced upstream regulator of p38 MAPK prevents TGF beta-induced p38 and MSK1 activity. MSK1 functionally regulates pro-apoptotic BH3-only BCL2 proteins, as MSK1 knockdown reduces Bad phosphorylation and enhances Noxa and Bim expression, leading to enhanced TGF beta-induced caspase-3 activity and cell death. This finding suggests that MSK1 represents a pro-survival pathway bifurcating downstream of p38 and antagonizes the established pro-apoptotic p38 MAPK function. Furthermore, EGF could reverse all the effects observed after MSK1 knockdown...Show moreTransforming growth factor-beta (TGF beta) binding to its receptor leads to intracellular phosphorylation of Smad2 and Smad3, which oligomerize with Smad4. These complexes accumulate in the nucleus and induce gene transcription. Here we describe mitogen-and stress-activated kinase 1 (MSK1) as an antagonist of TGF beta-induced cell death. Induction of MSK1 activity by TGF beta depends on Smad4 and p38 MAPK activation. Knockdown of GADD45, a Smad4-induced upstream regulator of p38 MAPK prevents TGF beta-induced p38 and MSK1 activity. MSK1 functionally regulates pro-apoptotic BH3-only BCL2 proteins, as MSK1 knockdown reduces Bad phosphorylation and enhances Noxa and Bim expression, leading to enhanced TGF beta-induced caspase-3 activity and cell death. This finding suggests that MSK1 represents a pro-survival pathway bifurcating downstream of p38 and antagonizes the established pro-apoptotic p38 MAPK function. Furthermore, EGF could reverse all the effects observed after MSK1 knockdown. Monitoring the status of MSK1 activity in cancer promises new therapeutic targets as inactivating both MSK1 and EGF signaling may (re)-sensitize cells to TGF beta-induced cell death.Show less

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TGF beta Activates Mitogen- and Stress-activated Protein Kinase-1 (MSK1) to Attenuate Cell Death