The integrin-binding protein talin stimulates invadopodia formation and tumor cell metastasis by recruiting the sodium/hydrogen exchanger NHE1, Beaty et al. reveal.
Tumor cells form actin-rich protrusions called invadopodia that degrade the extracellular matrix and facilitate cell invasion and metastasis. The adhesion receptor β1 integrin promotes invadopodial maturation, but whether integrin-associated proteins such as talin assist in this process is unknown. Beaty et al. found that talin localizes to invadopodial precursor structures and that knocking down talin prevented their maturation into matrix-degrading protrusions by inhibiting the recruitment of the sodium/hydrogen exchanger NHE-1.
NHE-1 promotes invadopodial maturation by increasing the local cytoplasmic pH, thereby activating the actin-severing protein cofilin to generate free barbed ends and stimulate actin polymerization. The researchers discovered that talin’s C terminus binds directly to the FERM domain of the ERM protein moesin, which, in turn, recruited NHE-1 into invadopodial precursors. Tumor cells lacking talin thus formed fewer invasive protrusions and showed reduced migration through their surrounding tissue when injected into mouse mammary glands. Accordingly, loss of talin impaired the tumor cells’ ability to enter the bloodstream and form metastases in the lung.
Talin localized to invadopodia independently of β1 integrin, but the adhesion receptor was nevertheless required to recruit moesin and NHE-1 into the protrusions. Lead author Brian Beaty therefore wants to investigate how talin and β1 integrin combine to regulate NHE-1 activity and cell invasion.
Text by Ben Short