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PMID:19560418

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Citation

Dougherty, MK, Ritt, DA, Zhou, M, Specht, SI, Monson, DM, Veenstra, TD and Morrison, DK (2009) KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. Mol. Cell 34:652-62

Abstract

Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca2+-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca2+-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic beta-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.

Links

PubMed PMC2737517 Online version:10.1016/j.molcel.2009.06.001

Keywords

Animals; COS Cells; Calcineurin/metabolism; Calcium Signaling; Cercopithecus aethiops; Extracellular Signal-Regulated MAP Kinases/metabolism; Humans; MAP Kinase Signaling System; Mice; Protein Kinases/analysis; Protein Kinases/chemistry; Protein Kinases/metabolism; Protein Kinases/physiology; Protein-Serine-Threonine Kinases/analysis; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/metabolism; Protein-Serine-Threonine Kinases/physiology; RNA Interference; Rats

Significance

Annotations

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

MOUSE:PP2BA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q3UVC0

F

Seeded From UniProt

complete

MOUSE:PP2BA

acts_upstream_of_or_within

GO:0019722: calcium-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:3610315

P

Seeded From UniProt

complete

MOUSE:PP2BA

acts_upstream_of_or_within

GO:0006470: protein dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KSR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63328

F

Seeded From UniProt

complete

MOUSE:KSR2

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KSR2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KSR1

enables

GO:0005078: MAP-kinase scaffold activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KSR1

acts_upstream_of_or_within

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KSR2

acts_upstream_of_or_within

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KSR2

enables

GO:0031434: mitogen-activated protein kinase kinase binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:KSR2

acts_upstream_of_or_within

GO:0019722: calcium-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:107164

P

Seeded From UniProt

complete

MOUSE:KSR2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KSR2

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KSR2

enables

GO:0005078: MAP-kinase scaffold activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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