Opposite roles of Kindlin orthologs in cell survival and proliferation. Issue 9 (20th July 2022)

• Record Type: Journal Article
• Authors: Zhevlakova, Irina; Xiong, Luyang; Liu, Huan; Dudiki, Tejasvi; Ciocea, Alieta; Podrez, Eugene; Byzova, Tatiana V.
• Is Part Of: Cell proliferation. Volume 55:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-20
• Subjects: Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.13280
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: 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 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. 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. 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. Abstract : Cell anchorage is critical for tissue morphogenesis and protection against dysplasia and cancer metastasis. Only transformed and circulating haematopoietic cells thrive without anchorage. The adhesive machinery of anchorage‐dependent and ‐independent cells is similar, with the exception of Kindlin orthologs, Kindlin 2 (K2) and Kindlin 3 (K3). Our study reveals paradoxically opposite roles of K2 and K3 in cell survival despite their identical functions in cell adhesion. K3 deficiency promotes human lymphoma growth and survival. K3 deficiency protects anchorage‐independent cells from apoptosis and promotes their proliferation, while K2 deficiency triggers apoptosis and diminishes proliferation in anchorage‐dependent cells. We further demonstrate that Kindlins' effects on proliferation rely upon the interaction between Kindlin and paxillin in both, anchorage‐dependent and ‐independent cells.