Opposite roles of Kindlin orthologs in cell survival and proliferation.

in Cell proliferation by Irina Zhevlakova, Luyang Xiong, Huan Liu, Tejasvi Dudiki, Alieta Ciocea, Eugene Podrez, Tatiana V Byzova

TLDR

  • The study investigates how cells survive and grow in different conditions. The authors found that two types of cells called Kindlin orthologs play opposite roles in cell survival and proliferation in anchorage-dependent and independent cells. They also found that these cells have a protein called paxillin that helps them stick to surfaces. The study has important implications for understanding how cells grow and could help us find new ways to treat diseases.

Abstract

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. 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. 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. 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.

Overview

  • The study investigates the role of Kindlin orthologs in cell survival and proliferation in anchorage-dependent and independent cells. The authors used in vivo and in vitro models and K3 and K2 knockdown and knockin cells to demonstrate the opposite roles of Kindlin's in cell survival. They found that depletion of K3 promotes cell proliferation and survival of anchorage-independent cells, while the absence of K2 in anchorage-dependent cells accelerates apoptosis and limits proliferation. The study identifies the key elements of the cell adhesion machinery in cell survival and tumour metastasis, proposing possible targets for tumour treatment.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions. The authors found that depletion of K3 promotes cell proliferation and survival of anchorage-independent cells, while the absence of K2 in anchorage-dependent cells accelerates apoptosis and limits proliferation. These findings suggest that Kindlin orthologs play opposite roles in cell survival and proliferation in anchorage-dependent and independent cells.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The authors identified the key elements of the cell adhesion machinery in cell survival and tumour metastasis, proposing possible targets for tumour treatment. Future research could further explore the mechanisms of anchorage dependence and the role of Kindlin orthologs in tumour progression and metastasis.
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