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Proximity biotinylation provides insight into the molecular composition of focal adhesions at the nanometer scale

Identification of proteins within nanometers of components in focal adhesions reveals potential targets for preventing metastasis. Focusing on focal adhesions Focal adhesions are protein complexes that link cells to the surrounding extracellular matrix, and their disassembly and reassembly are required during cell migration. The proteins in focal adhesions could be targeted to prevent cancer cell metastasis, but the composition of these complexes (which is generally referred to as the adhesome) has been controversial. Dong et al. used a label that targeted only proteins in close proximity to paxillin and β integrins, key components of focal adhesions. Mass spectrometry on the labeled proteins revealed that focal adhesions contained fewer proteins than previously suspected and identified several previously unknown components. After analysis of the function of these proteins in focal adhesions, they could be targeted to block metastasis. Focal adhesions are protein complexes that link metazoan cells to the extracellular matrix through the integrin family of transmembrane proteins. Integrins recruit many proteins to these complexes, referred to as the “adhesome.” We used proximity-dependent biotinylation (BioID) in U2OS osteosarcoma cells to label proteins within 15 to 25 nm of paxillin, a cytoplasmic focal adhesion protein, and kindlin-2, which directly binds β integrins. Using mass spectrometry analysis of the biotinylated proteins, we identified 27 known adhesome proteins and 8 previously unknown components close to paxillin. However, only seven of these proteins interacted directly with paxillin, one of which was the adaptor protein Kank2. The proteins in proximity to β integrin included 15 of the adhesion proteins identified in the paxillin BioID data set. BioID also correctly established kindlin-2 as a cell-cell junction protein. By focusing on this smaller data set, new partners for kindlin-2 were found, namely, the endocytosis-promoting proteins liprin β1 and EFR3A, but, contrary to previous reports, not the filamin-binding protein migfilin. A model adhesome based on both data sets suggests that focal adhesions contain fewer components than previously suspected and that paxillin lies away from the plasma membrane. These data not only illustrate the power of using BioID and stable isotope–labeled mass spectrometry to define macromolecular complexes but also enable the correct identification of therapeutic targets within the adhesome.