PI3Kβ links integrin activation and PI(3,4)P2 production during invadopodial maturation

Zahra Erami, Samantha Heitz, Anne R. Bresnick, Jonathan M. Backer

Research output: Contribution to journalArticle

Abstract

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)P2 by the phosphoinositide 5'-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P2, 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.

Original languageEnglish (US)
Pages (from-to)2367-2376
Number of pages10
JournalMolecular biology of the cell
Volume30
Issue number18
DOIs
StatePublished - Aug 15 2019

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Phosphatidylinositol 3-Kinases
Integrins
phosphoinositide 5-phosphatase
Breast Neoplasms
Neoplasms
Receptor Protein-Tyrosine Kinases
Metalloproteases
Chemotaxis
Gelatin
G-Protein-Coupled Receptors
phosphoinositide-3,4-bisphosphate
Organelles
Extracellular Matrix
Actins
Protein Isoforms
Podosomes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

PI3Kβ links integrin activation and PI(3,4)P2 production during invadopodial maturation. / Erami, Zahra; Heitz, Samantha; Bresnick, Anne R.; Backer, Jonathan M.

In: Molecular biology of the cell, Vol. 30, No. 18, 15.08.2019, p. 2367-2376.

Research output: Contribution to journalArticle

Erami, Zahra ; Heitz, Samantha ; Bresnick, Anne R. ; Backer, Jonathan M. / PI3Kβ links integrin activation and PI(3,4)P2 production during invadopodial maturation. In: Molecular biology of the cell. 2019 ; Vol. 30, No. 18. pp. 2367-2376.
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