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PMID:20660631

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Citation

Chao, WT, Daquinag, AC, Ashcroft, F and Kunz, J (2010) Type I PIPK-alpha regulates directed cell migration by modulating Rac1 plasma membrane targeting and activation. J. Cell Biol. 190:247-62

Abstract

Phosphatidylinositol-4,5-bisphosphate (PI4,5P(2)) is a critical regulator of cell migration, but the roles of the type I phosphatidylinositol-4-phosphate 5-kinases (PIPKIs), which synthesize PI4,5P(2), have yet to be fully defined in this process. In this study, we report that one kinase, PIPKI-alpha, is a novel upstream regulator of Rac1 that links activated integrins to the regulation of cell migration. We show that PIPKI-alpha controls integrin-induced translocation of Rac1 to the plasma membrane and thereby regulates Rac1 activation. Strikingly, this function is not shared with other PIPKI isoforms, is independent of catalytic activity, and requires physical interaction of PIPKI-alpha with the Rac1 polybasic domain. Consistent with its role in Rac1 activation, depletion of PIPKI-alpha causes pronounced defects in membrane ruffling, actin organization, and focal adhesion formation, and ultimately affects the directional persistence of migration. Thus, our study defines the role of PIPKI-alpha in cell migration and describes a new mechanism for the spatial regulation of Rac1 activity that is critical for cell migration.

Links

PubMed PMC2930278 Online version:10.1083/jcb.200911110

Keywords

Actins/metabolism; Animals; Cell Adhesion/physiology; Cell Membrane/metabolism; Cell Membrane/ultrastructure; Cell Movement/physiology; Enzyme Activation; HeLa Cells; Humans; Integrins/metabolism; Isoenzymes/genetics; Isoenzymes/metabolism; Phosphatidylinositol 4,5-Diphosphate/metabolism; Phosphotransferases (Alcohol Group Acceptor)/genetics; Phosphotransferases (Alcohol Group Acceptor)/metabolism; Protein Structure, Tertiary; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; rac1 GTP-Binding Protein/genetics; rac1 GTP-Binding Protein/metabolism

Significance

Annotations

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

HUMAN:RAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99755

F

Seeded From UniProt

complete

HUMAN:PI51A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63000

F

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0090630: activation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0031532: actin cytoskeleton reorganization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PI51A

located_in

GO:0032587: ruffle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PI51A

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0060326: cell chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0048041: focal adhesion assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PI51A

involved_in

GO:0097178: ruffle assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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