Proposed mechanisms involved in invadopodia formation under hypoxia.

<p>The hypoxic microenvironment in solid tumor is proposed to influence invadopodia formation through a biphasic mechanism involving the regulation of HDAC6, followed by activation of the TGFβ/Smad3-dependent signaling pathway. First, hypoxia leads to the activation of the EGF/EGFR pathway, which enhances HDAC6 tubulin deacetylase activity. In parallel, hypoxia increases the expression of the proprotein convertase furin, resulting in enhanced TGFβ processing and bioactivation. HDAC6 tubulin deacetylation may allow the desequestration of Smad3 from the MT network leading to its activation and nuclear translocation. Smad3 translocation leads to enhanced transcription of TGFβ inducible genes and invadopodia production. In this model, HDAC6 might also translocate to the cell periphery where it was shown to be involved in cortactin deacetylation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055529#pone.0055529-Kaluza1" target="_blank">[31]</a> an event needed for the formation of actin-rich invadopodia structures.