PMID:20179103

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
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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	occurs_in:(GO:0005829)	Seeded From UniProt	complete
HUMAN:RHG08	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q13526	F	occurs_in:(GO:0005634)	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	occurs_in:(GO:0005829)	Seeded From UniProt	complete
HUMAN:PIN1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P85298-4	F	occurs_in:(GO:0005634)	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	occurs_in:(GO:0005829)	Seeded From UniProt	complete
MOUSE:MP2K2	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P85298-4	F	occurs_in:(GO:0005829)	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

References

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