Abstract
Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
Highlights
Cell migration is vital for embryonic morphogenesis, tissue repair and regeneration, the immune response and in progression of diseases such as cancer [1,2]
Stress-inducible phosphoprotein 1 (STIP1) knockdown resulted in reduced formation of pseudopodia as well as decreased cell migration in a breast cancer cell line, where it colocalized with actin [59]
We have determined that murine STI1 (mSTI1) can bind Hsp70 and Hsp90 from human cell lysates, suggesting that mSTI1 can participate in similar interactions to STIP1
Summary
Cell migration is vital for embryonic morphogenesis, tissue repair and regeneration, the immune response and in progression of diseases such as cancer [1,2]. ATP-actin associates at the barbed end and ADP-actin disassociates from the pointed end in an essential process for migration known as actin treadmilling [9]. In addition to the ATPase activity of actin, F-actin formation, and cell migration, is regulated by protein–protein interactions [9,11], involving a core group of actin-binding proteins that include cofilin and profilin. Profilin and cofilin regulate actin polymerisation [15,16,17] and localization [18]. Profilin promotes the polymerisation of G-actin into F-actin filaments, whilst cofilin is responsible for disassembly of actin fibres [19,20]. Many of the actin regulatory proteins including cofilin and profilin are found in the nucleus, where they regulate polymerisation and localization of actin. Profilin is predominantly nuclear and acts as a cofactor with exportin-6 in the export of actin out of the nucleus [39,40]
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