Open AccessAbl-mediated PI3K activation regulates macrophage podosome formation
Author(s) -
Yuhuan Zhou,
Zhen Feng,
Fakun Cao,
Xiaoting Liu,
Xiaojie Xia,
Cheng-Ku Yu
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.234385
Subject(s) - podosome , microbiology and biotechnology , invadopodia , biology , proto oncogene tyrosine protein kinase src , cortactin , phosphorylation , tensin , phosphatidylinositol , actin , pi3k/akt/mtor pathway , signal transduction , pten , biochemistry , genetics , cytoskeleton , cancer , cancer cell , cell
Podosomes play critical roles in macrophage adhesion and migration. WASP-mediated actin polymerization is one of the key events initiating the podosome formation. Nevertheless, membrane signals to trigger WASP activation at macrophage podosomes remain unclear. Here, we find that PI(3,4,5)P3 lipids are enriched at the podosome and stably recruit WASP rather than WASP-5KE mutant. PIK3CB is spatially located at the podosome core. Inhibition of PIK3CB and overexpression of 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 PI3K regulatory subunits. Knockdown of Abl1 rather than Abl2 suppresses the PI3K/Akt pathway regardless of Src and Hck activities. Reintroduction of wildtype Abl1 rather than Abl1-Y488F mutant rescues PI3KR1 recruitment and PI3K activation. When each of PIK3CB, Abl1, and Src/Hck is suppressed, macrophage podosome formation, matrix degradation, and chemotactic migration are inhibited. Thus, Src/Hck-mediated Abl1 Tyr488 phosphorylation triggers PIK3CB-dependent PI(3,4,5)P3 production and orchestrates the assembly and function of macrophage podosome.