Conclusion
Kindlin ortologs and their interaction to cytoskeletal protein paxillin define the mechanisms of anchorage dependence. Our study identifies the key elements of the cell adhesion machinery in cell survival and tumour metastasis, proposing possible targets for tumour treatment.
Material and methods
To demonstrate the opposite roles of Kindlin's in cell survival we utilized in vivo and in vitro models and K3 and K2 knockdown and knockin cells. We used human lymphocytes from the K3 deficient patients in tumour model, K3 knockout and knockin macrophages and K2 knockout and knockin MEF cells for experiments in under conditions of adhesion and in suspension.
Methods
To demonstrate the opposite roles of Kindlin's in cell survival we utilized in vivo and in vitro models and K3 and K2 knockdown and knockin cells. We used human lymphocytes from the K3 deficient patients in tumour model, K3 knockout and knockin macrophages and K2 knockout and knockin MEF cells for experiments in under conditions of adhesion and in suspension.
Objective
It is unclear why adhesion-dependent cells such as epithelium undergo anoikis without anchorage, while adhesion-independent blood cells thrive in suspension. The adhesive machinery of these cells is similar, with the exception of Kindlin orthologs, Kindlin 2 (K2) and Kindlin 3 (K3). Here we address how Kindlins control cell survival and proliferation in anchorage-dependent and independent cells. Material and
Results
Depletion of K3 promotes cell proliferation and survival of anchorage-independent cells regardless of cell attachment. In contrast, the absence of K2 in anchorage-dependent cells accelerates apoptosis and limits proliferation. K3 deficiency promotes human lymphoma growth and survival in vivo. Kindlins' interaction with paxillin, is critical for their differential roles in cell anchorage. While disruption of K2-paxillin binding leads to increased apoptosis, the lack of K3-paxillin binding has an opposite effect in adhesion-independent cells.