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PMID:12912914

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Citation

Zegers, MM, Forget, MA, Chernoff, J, Mostov, KE, ter Beest, MB and Hansen, SH (2003) Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J. 22:4155-65

Abstract

Wound healing in epithelia requires coordinated cell migration and proliferation regulated by signaling mechanisms that are poorly understood. Here we show that epithelial cells expressing constitutively active or kinase-dead mutants of the Rac/Cdc42 effector Pak1 fail to undergo growth arrest upon wound closure. Strikingly, this phenotype is only observed when the Pak1 kinase mutants are expressed in cells possessing a free lateral surface, i.e. one that is not engaged in contact with neighboring cells. The Pak1 kinase mutants perturb contact inhibition by a mechanism that depends on the Pak-interacting Rac-GEF PIX. In control cells, endogenous activated Pak and PIX translocate from focal complexes to cell-cell contacts during wound closure. This process is abrogated in cells expressing Pak1 kinase mutants. In contrast, Pak1 mutants rendered defective in PIX binding do not impede translocation of activated Pak and PIX, and exhibit normal wound healing. Thus, recruitment of activated Pak and PIX to cell-cell contacts is pivotal to transduction of growth-inhibitory signals from neighboring cells in epithelial wound healing.

Links

PubMed PMC175788 Online version:10.1093/emboj/cdg398

Keywords

Animals; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Division; Cell Line; Cell Membrane/metabolism; Cell Movement; Contact Inhibition; Dogs; Enzyme Activation; Epithelial Cells/cytology; Epithelial Cells/enzymology; Epithelial Cells/metabolism; Gene Expression Regulation, Enzymologic; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; Humans; Kidney/cytology; Kinetics; Mutation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Wound Healing; p21-Activated Kinases

Significance

Annotations

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

HUMAN:PAK1

located_in

GO:0001726: ruffle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAK1

located_in

GO:0005911: cell-cell junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAK1

part_of

GO:0001726: ruffle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAK1

part_of

GO:0005911: cell-cell junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAK1

involved_in

GO:0042060: wound healing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAK1

involved_in

GO:0060244: negative regulation of cell proliferation involved in contact inhibition

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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