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Article: Abl-mediated PI3K activation regulates macrophage podosome formation

TitleAbl-mediated PI3K activation regulates macrophage podosome formation
Authors
KeywordsAbl
PI(3,4,5)P3 lipid
PI3K
Podosome
Issue Date2020
PublisherThe Company of Biologists Ltd.
Citation
Journal of Cell Science, 2020, v. 133 n. 11, p. article no. jcs234385 How to Cite?
AbstractPodosomes play crucial roles in macrophage adhesion and migration. Wiskott–Aldrich syndrome protein (WASP; also known as WAS)-mediated actin polymerization is one of the key events initiating podosome formation. Nevertheless, membrane signals to trigger WASP activation at macrophage podosomes remain unclear. Here, we show that phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] lipids are enriched at the podosome and stably recruit WASP rather than the WASP-5KE mutant. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB) is spatially located at the podosome core. Inhibition of PIK3CB and overexpression of phosphatase and tensin homolog (PTEN) impede F-actin polymerization of the podosome. PIK3CB activation is regulated by Abl1 and Src family kinases. At the podosome core, Src and Hck promote the phosphorylation of Tyr488 in the consensus Y-x-x-M motif of Abl1, which enables the association of phosphoinositide 3-kinase (PI3K) regulatory subunits. Knockdown of Abl1 rather than Abl2 suppresses the PI3K/Akt pathway, regardless of Src and Hck activities. Reintroduction of wild-type Abl1 rather than the Abl1-Y488F mutant rescues PI3KR1 recruitment and PI3K activation. When PIK3CB, Abl1 or Src/Hck is suppressed, macrophage podosome formation, matrix degradation and chemotactic migration are inhibited. Thus, Src/Hck-mediated phosphorylation of Abl1 Tyr488 triggers PIK3CB-dependent PI(3,4,5)P3 production and orchestrates the assembly and function of macrophage podosomes.
Descriptioneid_2-s2.0-85086283072link_to_subscribed_fulltext
Persistent Identifierhttp://hdl.handle.net/10722/288403
ISSN
2019 Impact Factor: 4.573
2015 SCImago Journal Rankings: 3.501

 

DC FieldValueLanguage
dc.contributor.authorZHOU, Y-
dc.contributor.authorFENG, Z-
dc.contributor.authorCAO, F-
dc.contributor.authorLIU, X-
dc.contributor.authorXIA, X-
dc.contributor.authorYu, CH-
dc.date.accessioned2020-10-05T12:12:22Z-
dc.date.available2020-10-05T12:12:22Z-
dc.date.issued2020-
dc.identifier.citationJournal of Cell Science, 2020, v. 133 n. 11, p. article no. jcs234385-
dc.identifier.issn0021-9533-
dc.identifier.urihttp://hdl.handle.net/10722/288403-
dc.descriptioneid_2-s2.0-85086283072link_to_subscribed_fulltext-
dc.description.abstractPodosomes play crucial roles in macrophage adhesion and migration. Wiskott–Aldrich syndrome protein (WASP; also known as WAS)-mediated actin polymerization is one of the key events initiating podosome formation. Nevertheless, membrane signals to trigger WASP activation at macrophage podosomes remain unclear. Here, we show that phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] lipids are enriched at the podosome and stably recruit WASP rather than the WASP-5KE mutant. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB) is spatially located at the podosome core. Inhibition of PIK3CB and overexpression of phosphatase and tensin homolog (PTEN) impede F-actin polymerization of the podosome. PIK3CB activation is regulated by Abl1 and Src family kinases. At the podosome core, Src and Hck promote the phosphorylation of Tyr488 in the consensus Y-x-x-M motif of Abl1, which enables the association of phosphoinositide 3-kinase (PI3K) regulatory subunits. Knockdown of Abl1 rather than Abl2 suppresses the PI3K/Akt pathway, regardless of Src and Hck activities. Reintroduction of wild-type Abl1 rather than the Abl1-Y488F mutant rescues PI3KR1 recruitment and PI3K activation. When PIK3CB, Abl1 or Src/Hck is suppressed, macrophage podosome formation, matrix degradation and chemotactic migration are inhibited. Thus, Src/Hck-mediated phosphorylation of Abl1 Tyr488 triggers PIK3CB-dependent PI(3,4,5)P3 production and orchestrates the assembly and function of macrophage podosomes.-
dc.languageeng-
dc.publisherThe Company of Biologists Ltd. -
dc.relation.ispartofJournal of Cell Science-
dc.subjectAbl-
dc.subjectPI(3,4,5)P3 lipid-
dc.subjectPI3K-
dc.subjectPodosome-
dc.titleAbl-mediated PI3K activation regulates macrophage podosome formation-
dc.typeArticle-
dc.identifier.emailYu, CH: chyu1@hku.hk-
dc.identifier.authorityYu, CH=rp01930-
dc.identifier.doi10.1242/jcs.234385-
dc.identifier.pmid32393599-
dc.identifier.scopuseid_2-s2.0-85086283072-
dc.identifier.hkuros315369-
dc.identifier.volume133-
dc.identifier.issue11-
dc.identifier.spagearticle no. jcs234385-
dc.identifier.epagearticle no. jcs234385-
dc.publisher.placeUnited Kingdom-

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