Biochemical analysis of MST1 kinase: elucidation of a C-terminal regulatory region.
The MST1 kinase phosphorylates FoxO transcription factors in the cytosol and histone H2B in the nucleus to promote cellular apoptosis. In addition to a N-terminal kinase domain, MST1 contains C-terminal regulatory and dimerization regions that are cleaved upon nuclear transport. In this report, we investigate the role of the MST1 regulatory region and dimerization domain in MST1 activity toward FoxO and histone H2B substrates. We find that the MST1 regulatory region enhances FoxO phosphorylation while inhibiting histone H2B phosphorylation, consistent with the cellular properties of MST1. We also identify autophosphorylation sites within the MST1 regulatory region and show that both regulatory region phosphorylation and MST1 dimerization contribute to FoxO phosphorylation. Together, our studies provide new insights into how MST1 substrate selectivity is modulated with implications for understanding apoptotic signaling through MST1 kinase.
Anand
Ruchi
R
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Kim
Ah-Young
AY
Brent
Michael
M
Marmorstein
Ronen
R
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D013379:Substrate Specificity; D000099317:Hippo Kinases
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; C085126:FOXO1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases