PI3Kβ links integrin activation and PI(3,4)P 2 production during invadopodial maturation

The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously report...

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Bibliographic Details
Published in:Molecular biology of the cell 2019-08, Vol.30 (18), p.2367-2376
Main Authors: Erami, Zahra, Heitz, Samantha, Bresnick, Anne R, Backer, Jonathan M
Format: Article
Language:English
Subjects:
Actins - metabolism
Breast Neoplasms - metabolism
Cell Line, Tumor
Chemotaxis - physiology
Extracellular Matrix - metabolism
Female
Humans
Integrins - metabolism
Integrins - physiology
Neoplasm Invasiveness - pathology
Phosphatidylinositol 3-Kinase - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Phosphatidylinositols - metabolism
Phosphorylation
Podosomes - metabolism
Podosomes - physiology
Signal Transduction - physiology
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Summary:The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein-coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P by the phosphoinositide 5'-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E19-03-0182