Phosphoinositide 3-kinase p85beta regulates invadopodium formation.

Ariel E Cariaga-Martínez,Vicente Pérez-García,Ana C Carrera,Javier Redondo-Muñóz,Isabel Cortés,Esther García,Inés M Antón,María J Pajares,Miguel A Idoate

doi:10.1242/bio.20148185

Ariel E Cariaga-Martínez, Vicente Pérez-García + Show 7 more

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https://doi.org/10.1242/bio.20148185

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Abstract

ABSTRACTThe acquisition of invasiveness is characteristic of tumor progression. Numerous genetic changes are associated with metastasis, but the mechanism by which a cell becomes invasive remains unclear. Expression of p85β, a regulatory subunit of phosphoinositide-3-kinase, markedly increases in advanced carcinoma, but its mode of action is unknown. We postulated that p85β might facilitate cell invasion. We show that p85β localized at cell adhesions in complex with focal adhesion kinase and enhanced stability and maturation of cell adhesions. In addition, p85β induced development at cell adhesions of an F-actin core that extended several microns into the cell z-axis resembling the skeleton of invadopodia. p85β lead to F-actin polymerization at cell adhesions by recruiting active Cdc42/Rac at these structures. In accordance with p85β function in invadopodium-like formation, p85β levels increased in metastatic melanoma and p85β depletion reduced invadopodium formation and invasion. These results show that p85β enhances invasion by inducing cell adhesion development into invadopodia-like structures explaining the metastatic potential of tumors with increased p85β levels.

Highlights

Cell invasion is a complex process that involves cell adhesion, polarization and formation of invasive structures (Morgan et al, 2007; Block et al, 2008)
We show that p85b localizes at cell adhesions in complex with focal adhesion kinase (FAK). p85b expression stabilized focal adhesions and mediated formation of cell adhesions that extend several microns into the z-axis and have an F-actin core, similar to that of invadopodia. p85b depletion reduced the depth and GTP-Cdc42/Rac levels of cell adhesions, suggesting that p85b functions by recruiting these active GTPases to cell adhesions. p85b overexpression was frequent in metastatic melanoma, and its depletion in an invasive melanoma cell line impaired invadopodium formation and invasion
The presented results show that p85b in complex with FAK localizes at cell adhesions and mediates their stabilization, maturation, and z-axis actin polymerization

Summary

Introduction

Cell invasion is a complex process that involves cell adhesion, polarization and formation of invasive structures (Morgan et al, 2007; Block et al, 2008). There are several types of cell adhesions; focal contacts are shell-shaped adhesion structures that form immediately behind the cell leading edge and are transformed into longer structures termed focal adhesions that provide firm adhesion via actomyosin stress fibers. These focal adhesions in turn develop into centrally located fibrillar adhesions, sites of fibronectin matrix deposition that mediate strong adhesion. Cell adhesions are highly dynamic structures containing proteins that include focal adhesion kinase (FAK), talin, paxillin and vinculin, some of which connect integrin receptors with the actomyosin fibers (Morgan et al, 2007; Block et al, 2008; Wolfenson et al, 2013)

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