The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1.
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.
Cinar
Bekir
B
Urological Diseases Research Center, Department of Urology, Children's Hospital Boston, Boston, MA, USA.
Fang
Ping-Ke
PK
Lutchman
Mohini
M
Di Vizio
Dolores
D
Adam
Rosalyn M
RM
Pavlova
Natalya
N
Rubin
Mark A
MA
Yelick
Pamela C
PC
Freeman
Michael R
MR
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D021962:Membrane Microdomains / Q000737:chemistry; D008954:Models, Biological; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015027:Zebrafish; D000099317:Hippo Kinases
D020169:Caspases; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C095566:STK4 protein, human; D000099317:Hippo Kinases; C494918:AKT1 protein, human