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PMID:19962960

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Citation

Song, H, Oh, S, Oh, HJ and Lim, DS (2010) Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity. Biochem. Biophys. Res. Commun. 391:969-73

Abstract

The tumor suppressor, RASSF2 (Ras association domain family 2), is frequently downregulated in a number of cancers. Although exogenously expressed RASSF2 induces apoptotic cell death, the precise roles of RASSF2 under pro-apoptotic conditions remain largely unknown. Here, we demonstrate that MST1 (mammalian sterile 20-like kinase 1) regulates RASSF2 protein stability. Knockdown of MST1 in cancer cells markedly destabilizes RASSF2, and Mst1-deficient mice show reduced Rassf2 protein levels in several organs. Conversely, RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex, which inhibits the MST-FOXO3 signaling pathway. RASSF2 also engages the JNK pathway and induces apoptosis in an MST1-independent manner. Collectively, these findings indicate that MST1 is a major determinant of RASSF2 protein stability, and suggest that RASSF2 acts in a complex manner that extends beyond simple protein-protein association to play an important role in MST1 regulation.

Links

PubMed Online version:10.1016/j.bbrc.2009.11.175

Keywords

Animals; Apoptosis; Cell Line; Enzyme Activation; Forkhead Transcription Factors/metabolism; Gene Knockdown Techniques; Humans; MAP Kinase Kinase 4/metabolism; Mice; Mice, Knockout; Neoplasms/enzymology; Protein Stability; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

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

HUMAN:RASF2

acts_upstream_of_or_within

GO:0043065: positive regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RASF2

acts_upstream_of_or_within

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RASF2

acts_upstream_of_or_within

GO:0046330: positive regulation of JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RASF2

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RASF2

acts_upstream_of_or_within

GO:0031954: positive regulation of protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RASF2

acts_upstream_of_or_within

GO:0033137: negative regulation of peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RASF2

enables

GO:0004672: protein kinase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q13043

F

Seeded From UniProt

complete

HUMAN:STK4

acts_upstream_of_or_within

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STK4

acts_upstream_of_or_within

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STK4

acts_upstream_of_or_within

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RASF2

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

P

Seeded From UniProt

complete

MOUSE:RASF2

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

P

Seeded From UniProt

complete

MOUSE:RASF2

involved_in

GO:0046330: positive regulation of JNK cascade

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

P

Seeded From UniProt

complete

MOUSE:RASF2

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

C

Seeded From UniProt

complete

MOUSE:RASF2

enables

GO:0004672: protein kinase activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

F

Seeded From UniProt

complete

MOUSE:RASF2

involved_in

GO:0031954: positive regulation of protein autophosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

P

Seeded From UniProt

complete

MOUSE:RASF2

involved_in

GO:0033137: negative regulation of peptidyl-serine phosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P50749

P

Seeded From UniProt

complete

MOUSE:STK4

involved_in

GO:0050821: protein stabilization

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK4

involved_in

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK4

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK4

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4414818

P

Seeded From UniProt

complete

HUMAN:STK4

involved_in

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STK4

involved_in

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STK4

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STK4

enables

GO:0004672: protein kinase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P50749

F

Seeded From UniProt

complete

HUMAN:STK4

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STK3

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK4

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

C

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0050821: protein stabilization

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4414818

P

Seeded From UniProt

complete

MOUSE:STK4

enables

GO:0004672: protein kinase activity

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

F

Seeded From UniProt

complete

MOUSE:STK4

acts_upstream_of_or_within

GO:0001934: positive regulation of protein phosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13043

P

Seeded From UniProt

complete

MOUSE:STK3

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q13188

C

Seeded From UniProt

complete

Notes

See also

References

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