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PMID:21295697

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Citation

Wu, X, Shen, QT, Oristian, DS, Lu, CP, Zheng, Q, Wang, HW and Fuchs, E (2011) Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β. Cell 144:341-52

Abstract

Homeostasis and wound healing rely on stem cells (SCs) whose activity and directed migration are often governed by Wnt signaling. In dissecting how this pathway integrates with the necessary downstream cytoskeletal dynamics, we discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. Phosphorylation-refractile ACF7 rescues overall microtubule architecture, but phosphorylation-constitutive mutants do not. Neither mutant rescues polarized movement, revealing that phospho-regulation must be dynamic. This circuitry is physiologically relevant and depends upon polarized GSK3β inhibition at the migrating front of SCs/progeny streaming from HFs during wound repair. Moreover, only ACF7 and not GSKβ-refractile-ACF7 restore polarized microtubule-growth and SC-migration to ACF7 null skin. Our findings provide insights into how this conserved spectraplakin integrates signaling, cytoskeletal dynamics, and polarized locomotion of somatic SCs.

Links

PubMed PMC3050560 Online version:10.1016/j.cell.2010.12.033

Keywords

Animals; Cell Movement; Cells, Cultured; Glycogen Synthase Kinase 3/metabolism; Mice; Mice, Transgenic; Microfilament Proteins/metabolism; Microtubules/metabolism; Phosphorylation; Protein Structure, Tertiary; Skin/cytology; Skin/metabolism; Stem Cells/cytology; Stem Cells/metabolism; Wound Healing

Significance

Annotations

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

MOUSE:MACF1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MACF1

involved_in

GO:0032886: regulation of microtubule-based process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MACF1

involved_in

GO:0010632: regulation of epithelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MACF1

located_in

GO:0005874: microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MACF1

involved_in

GO:0042060: wound healing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3B

involved_in

GO:0032886: regulation of microtubule-based process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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