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PMID:16417406

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Citation

Weiner, OD, Rentel, MC, Ott, A, Brown, GE, Jedrychowski, M, Yaffe, MB, Gygi, SP, Cantley, LC, Bourne, HR and Kirschner, MW (2006) Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis. PLoS Biol. 4:e38

Abstract

Migrating cells need to make different actin assemblies at the cell's leading and trailing edges and to maintain physical separation of signals for these assemblies. This asymmetric control of activities represents one important form of cell polarity. There are significant gaps in our understanding of the components involved in generating and maintaining polarity during chemotaxis. Here we characterize a family of complexes (which we term leading edge complexes), scaffolded by hematopoietic protein 1 (Hem-1), that organize the neutrophil's leading edge. The Wiskott-Aldrich syndrome protein family Verprolin-homologous protein (WAVE)2 complex, which mediates activation of actin polymerization by Rac, is only one member of this family. A subset of these leading edge complexes are biochemically separable from the WAVE2 complex and contain a diverse set of potential polarity-regulating proteins. RNA interference-mediated knockdown of Hem-1-containing complexes in neutrophil-like cells: (a) dramatically impairs attractant-induced actin polymerization, polarity, and chemotaxis; (b) substantially weakens Rac activation and phosphatidylinositol-(3,4,5)-tris-phosphate production, disrupting the (phosphatidylinositol-(3,4,5)-tris-phosphate)/Rac/F-actin-mediated feedback circuit that organizes the leading edge; and (c) prevents exclusion of activated myosin from the leading edge, perhaps by misregulating leading edge complexes that contain inhibitors of the Rho-actomyosin pathway. Taken together, these observations show that versatile Hem-1-containing complexes coordinate diverse regulatory signals at the leading edge of polarized neutrophils, including but not confined to those involving WAVE2-dependent actin polymerization.

Links

PubMed PMC1334198 Online version:10.1371/journal.pbio.0040038

Keywords

Actins/metabolism; Animals; Cell Line; Cell Polarity; Chemotaxis; Enzyme Activation; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism; Molecular Sequence Data; Myosins/metabolism; Neutrophils/cytology; Neutrophils/metabolism; Phosphatidylinositol Phosphates/biosynthesis; Phosphorylation; Protein Binding; Protein Subunits/metabolism; Reactive Oxygen Species/metabolism; Terminology as Topic; Wiskott-Aldrich Syndrome Protein Family/metabolism; rac GTP-Binding Proteins/metabolism

Significance

Annotations

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

HUMAN:MYPT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:SFPQ

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:AKT2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:NSF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14457

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31751

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8NEB9

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P98171

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14974

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y6D6

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IZP0

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15233

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P23246

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46459

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8TD16

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13459

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y6W5

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09666

F

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0030866: cortical actin cytoskeleton organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0030838: positive regulation of actin filament polymerization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0030593: neutrophil chemotaxis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0042327: positive regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0030011: maintenance of cell polarity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0006935: chemotaxis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NCKPL

part_of

GO:0031209: SCAR complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0030295: protein kinase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0005096: GTPase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCKPL

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0070358: actin polymerization-dependent cell motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCKPL

involved_in

GO:0035509: negative regulation of myosin-light-chain-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RHG04

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:AHNK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:MYO9B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:BECN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:NONO

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:ABI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:PK3C3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:BICD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:BIG1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete

HUMAN:WASF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P55160

F

Seeded From UniProt

complete


See also

References

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