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PMID:20179103

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Citation

Pan, CQ, Liou, YC and Low, BC (2010) Active Mek2 as a regulatory scaffold that promotes Pin1 binding to BPGAP1 to suppress BPGAP1-induced acute Erk activation and cell migration. J. Cell. Sci. 123:903-16

Abstract

BPGAP1 is a multidomain Rho GTPase-activating protein (RhoGAP) that promotes Erk activation and cell motility. However, the molecular mechanism of how these two processes are linked and regulated remains unclear. Here, we show that the RhoGAP domain of BPGAP1 interacts with the peptidyl-prolyl cis/trans isomerase (PPI) Pin1, leading to enhanced GAP activity towards RhoA. BPGAP1 also interacted with wild-type and constitutively active Mek2, but not with its kinase-dead mutant. However, only active Mek2 could bind Pin1, acting as a scaffold to bridge Pin1 and BPGAP1 in a manner that involves the release of an autoinhibited proline-rich motif, 186-PPLP-189, proximal to the RhoGAP domain. This allows the non-canonical 186-PPLP-189 and 256-DDYGD-260 motifs of the proline-rich region and RhoGAP domain of BPGAP1 to become accessible to concerted binding by the WW and PPI domains of Pin1, respectively. Interestingly, Pin1 knockdown led to 'super-induction' of BPGAP1-induced acute, but not chronic, Erk activation upon epidermal growth factor stimulation, in a process independent of GAP modulation. Reintroducing Pin1, but not its catalytic or non-binding mutants, reversed the effect and inhibited cell migration induced by coexpression of BPGAP1 and active Mek2. Thus, Pin1 regulates BPGAP1 function in Rho and Erk signalling, with active Mek2 serving as a novel regulatory scaffold that promotes crosstalk between RhoGAP, Pin1 and Erk in the regulation of cell migration.

Links

PubMed Online version:10.1242/jcs.064162

Keywords

Amino Acid Sequence; Animals; Binding Sites; Cell Line; Cell Movement; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/metabolism; GTPase-Activating Proteins/chemistry; GTPase-Activating Proteins/metabolism; Humans; MAP Kinase Kinase 2/metabolism; Mice; Models, Biological; Molecular Sequence Data; Peptidylprolyl Isomerase/metabolism; Proline-Rich Protein Domains; Protein Binding; Protein Structure, Tertiary

Significance

Annotations

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

HUMAN:RAF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

MOUSE:MP2K1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

HUMAN:RHG08

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q63932

F

Seeded From UniProt

complete

HUMAN:RHG08

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

HUMAN:RHG08

enables

GO:0005096: GTPase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RHG08

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RHG08

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q63932

F

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P85298-4

F

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31938

F

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04049

F

Seeded From UniProt

complete

MOUSE:MP2K2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

MOUSE:MP2K2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P85298-4

F

Seeded From UniProt

complete

MOUSE:MP2K2

enables

GO:0060090: molecular adaptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MP2K2

involved_in

GO:2000147: positive regulation of cell motility

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MP2K2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13526

F

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:2000146: negative regulation of cell motility

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0032794: GTPase activating protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P85298

F

Seeded From UniProt

complete

HUMAN:PIN1

involved_in

GO:0043547: positive regulation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PIN1

enables

GO:0031434: mitogen-activated protein kinase kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q63932

F

Seeded From UniProt

complete

HUMAN:PIN1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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