The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1

Abstract

Akt kinases mediate cell growth and survival. Here, we report that a pro‐apoptotic kinase, Mst1/STK4, is a physiological Akt1 interaction partner. Mst1 was identified as a component of an Akt1 multiprotein complex isolated from lipid raft‐enriched fractions of LNCaP human prostate cancer cells. Endogenous Mst1, along with its paralog, Mst2, acted as inhibitors of endogenous Akt1. Surprisingly, mature Mst1 as well as both of its caspase cleavage products, which localize to distinct subcellular compartments and are not structurally homologous, complexed with and inhibited Akt1. cRNAs encoding full‐length Mst1, and N‐ and C‐terminal caspase Mst1 cleavage products, reverted an early lethal phenotype in zebrafish development induced by expression of membrane‐targeted Akt1. Mst1 and Akt1 localized to identical subcellular sites in human prostate tumors. Mst1 levels declined with progression from clinically localized to hormone refractory disease, coinciding with an increase in Akt activation with transition from hormone naïve to hormone‐resistant metastases. These results position Mst1/2 within a novel branch of the phosphoinositide 3‐kinase/Akt pathway and suggest an important role in cancer progression.

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

“…7). Because Mst1 and Akt are reciprocally inhibitory (22,43), it is conceivable that they may repress each other to orchestrate the fine balance of TCR signals needed to regulate Foxp3 expression and Treg development.…”

“…Mst1 induces apoptosis through caspase-mediated proteolytic activation and histone H2B phosphorylation (19), or by enhancing Foxo1/3 nuclear entry through phosphorylation of Foxo1 and Foxo3 at S212 and S207, respectively, in fibroblasts and granule neurons (20,21). Mst1/2 proteins may also promote apoptosis by interacting and suppressing Akt activation in cancer cells (22). However, T cells from Mst1-deficient mice and human patients exhibit enhanced apoptosis (23)(24)(25) in addition to the mutant phenotypes of impaired adhesion and migration in mice (25)(26)(27)(28)(29), suggesting that Mst1 may exert different cellular functions in tissue/cell type-specific manners (28 …”

Germinal center kinases in immune regulation

“…[18][19][20][21][22][23] MST1 has been implicated in T-cell biology, as mice lacking MST1 exhibit a variety of T-cell abnormalities. 24 Cross-talk between MST1 and Akt appears able to antagonize Akt1 activity, 25 which is involved in T-cell costimulation and the regulation of NF-kB-dependent gene transcription. MST1 negatively regulates the activation and proliferative response of naive T cells.…”

MicroRNA-133b is a key promoter of cervical carcinoma development through the activation of the ERK and AKT1 pathways

“…Among the approximately 400 potential targets predicted by TargetScan (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) and PicTar (New York University, New York, NY, USA) programs (Lewis et al, 2003;Krek et al, 2005), MST2 is an important known tumor suppressor known to effect MAPK and AKT signaling activities in several diseases (Cinar et al, 2007;Mumby, 2007). MST2 mRNA contains a 3 0 -untranslated region (UTR) partially complementary to miR-133b, which is highly conserved among human, mouse and rat orthologs (Figure 5a).…”