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PMID:18070883

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Citation

Edwin, F and Patel, TB (2008) A novel role of Sprouty 2 in regulating cellular apoptosis. J. Biol. Chem. 283:3181-90

Abstract

Sprouty (SPRY) proteins modulate receptor-tyrosine kinase signaling and, thereby, regulate cell migration and proliferation. Here, we have examined the role of endogenous human SPRY2 (hSPRY2) in the regulation of cellular apoptosis. Small inhibitory RNA-mediated silencing of hSPRY2 abolished the anti-apoptotic action of serum in adrenal cortex adenocarcinoma (SW13) cells. Silencing of hSPRY2 decreased serum- or epidermal growth factor (EGF)-elicited activation of AKT and ERK1/2 and reduced the levels of EGF receptor. Silencing of hSPRY2 also inhibited serum-induced activation of p90RSK and decreased phosphorylation of pro-apoptotic protein BAD (BCL2-antagonist of cell death) by p90RSK. Inhibiting both the ERK1/2 and AKT pathways abolished the ability of serum to protect against apoptosis, mimicking the effects of silencing hSPRY2. Serum transactivated the EGF receptor (EGFR), and inhibition of the EGFR by a neutralizing antibody attenuated the anti-apoptotic actions of serum. Consistent with the role of EGFR and perhaps other growth factor receptors in the anti-apoptotic actions of serum, the tyrosine kinase binding domain of c-Cbl (Cbl-TKB) protected against down-regulation of the growth factor receptors such as EGFR and preserved the anti-apoptotic actions of serum when hSpry2 was silenced. Additionally, silencing of Spry2 in c-Cbl null cells did not alter the ability of serum to promote cell survival. Moreover, reintroduction of wild type hSPRY2, but not its mutants that do not bind c-Cbl or CIN85 into SW13 cells after endogenous hSPRY2 had been silenced, restored the anti-apoptotic actions of serum. Overall, we conclude that endogenous hSPRY2-mediated regulation of apoptosis requires c-Cbl and is manifested by the ability of hSPRY2 to sequester c-Cbl and thereby augment signaling via growth factor receptors.

Links

PubMed PMC2527238 Online version:10.1074/jbc.M706567200

Keywords

Adenocarcinoma/metabolism; Adrenal Cortex/pathology; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/physiology; Kidney Neoplasms/metabolism; Proto-Oncogene Proteins c-cbl/metabolism; RNA/metabolism; Receptor, Epidermal Growth Factor/metabolism; Receptors, Growth Factor/metabolism; Transcriptional Activation

Significance

Annotations

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

HUMAN:SPY2

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SPY2

enables

GO:0043539: protein serine/threonine kinase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SPY2

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SPY2

involved_in

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SPY2

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SPY2

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CBL

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0043066: negative regulation of apoptosis

IMP: Inferred from Mutant Phenotype: :

P


HUMAN:EGFR_original

GO:0046777: protein autophosphorylation

IMP: Inferred from Mutant Phenotype: :

P


HUMAN:EGFR_original

GO:0043066: negative regulation of apoptosis

IMP: Inferred from Mutant Phenotype:

P


HUMAN:EGFR_original

GO:0046777: protein autophosphorylation

IMP: Inferred from Mutant Phenotype:

P


HUMAN:EGFR

involved_in

GO:0046777: protein autophosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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