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PMID:16930133

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Citation

Callus, BA, Verhagen, AM and Vaux, DL (2006) Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J. 273:4264-76

Abstract

Genetic screens in Drosophila have revealed that the serine/threonine kinase Hippo (Hpo) and the scaffold protein Salvador participate in a pathway that controls cell proliferation and apoptosis. Hpo most closely resembles the pro-apoptotic mammalian sterile20 kinases 1 and 2 (Mst1 and 2), and Salvador (Sav) has a human orthologue hSav (also called hWW45). Here we show that Mst and hSav heterodimerize in an interaction requiring the conserved C-terminal coiled-coil domains of both proteins. hSav was also able to homodimerize, but this did not require its coiled-coil domain. Coexpression of Mst and hSav led to phosphorylation of hSav and also increased its abundance. In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav, whereas catalytically inactive Mst mutants that retained the ability to bind to hSav were still able to increase its abundance, although they were no longer able to phosphorylate hSav. Together these results show that hSav can bind to, and be phosphorylated by, Mst, and that the stabilizing effect of Mst on hSav requires its interaction with hSav but is probably not due to phosphorylation of hSav by Mst.

Links

PubMed Online version:10.1111/j.1742-4658.2006.05427.x

Keywords

Animals; Cell Cycle Proteins/chemistry; Cell Cycle Proteins/isolation & purification; Cell Cycle Proteins/metabolism; Cell Line; Dimerization; Gene Deletion; Humans; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/metabolism; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:STK4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H4B6

F

Seeded From UniProt

complete

HUMAN:STK3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H4B6

F

Seeded From UniProt

complete

HUMAN:SAV1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H4B6

F

Seeded From UniProt

complete

HUMAN:SAV1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13043

F

Seeded From UniProt

complete

HUMAN:SAV1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13188

F

Seeded From UniProt

complete

HUMAN:STK4

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000269: experimental evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:STK3

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000269: experimental evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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