Ca2+/S100 proteins inhibit the interaction of FKBP38 with Bcl-2 and Hsp90

Abstract

FKBP38 (FK506-binding protein 38), a membrane-anchored TPR (tetratricopeptide repeat)-containing immunophilin, regulates signalling pathways such as cell survival, apoptosis, proliferation and metastasis. However, the mechanisms that regulate the activity of FKBP38 are, at present, poorly understood. We previously reported that Ca2+/S100 proteins directly associate with the TPR proteins, such as Hop [Hsp70 (heat-shock protein of 70 kDa)/Hsp90-organizing protein], kinesin-light chain, Tom70 (translocase of outer mitochondrial membrane 70), FKBP52, CyP40 (cyclophilin 40), CHIP (C-terminus of Hsc70-interacting protein) and PP5 (protein phosphatase 5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore we have hypothesized that Ca2+/S100 proteins can interact with FKBP38 and regulate its function. In vitro binding studies demonstrated that S100A1, S100A2, S100A6, S100B and S100P specifically interact with FKBP38 and inhibit the interaction of FKBP38 with Bcl-2 and Hsp90. Overexpression of permanently active S100P in Huh-7 cells inhibited the interaction of FKBP38 with Bcl-2, resulting in the suppression of Bcl-2 stability. The association of the S100 proteins with FKBP38 provides a Ca2+-dependent regulatory mechanism of the FKBP38-mediated signalling pathways.

Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors

“…Based on published literature, the pathway building analysis predicted the interconnection among all genes utilized for the analysis. For instance, the analysis projected that upregulation of the calcium binding protein S100P leads to downregulation of Bcl‐2 (Shimamoto et al., 2014), which we found to be true when mifepristone induced cell death in combination with PI3K inhibitors (Wempe et al., 2013). S100P is predicted to increase expression of ezrin, which is confirmed in our results in SKOV‐3 cells (see Table S6).…”

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

“…Several studies have demonstrated that Ca 2+ ‐S100 proteins (S100A2, S100P, S100A6, S100A12, S100A1) associate with tetratricopeptide repeat (TPR)‐containing proteins (Shimamoto et al ., , , , ; Yamaguchi et al ., ; Maciejewski et al ., ). TPR‐containing proteins mediate protein–protein interactions and participate in the ordered assembly of heat shock proteins (HSP) HSP70–HSP90 into multichaperone complexes with their client proteins (Blatch & Lassle, ; Scheufler et al ., ).…”

The S100B story: from biomarker to active factor in neural injury

“…Intracellularly, S100B, as a calcium-sensor protein, appears to regulate a variety of activities, transferring signals from second messengers and interacting with different molecules in different cell types. In particular, S100B intervenes in cell proliferation, survival and differentiation (Baudier et al 1992;Millward et al 1998;Arcuri et al 2005;Raponi et al 2007;Saito et al 2007;Riuzzi et al 2011;Shimamoto et al 2014;Li et al 2016), participates in the regulation of cellular calcium homeostasis and enzyme activities (Zimmer and Van Eldik 1986;Heierhorst et al 1996;Pozdnyakov et al 1997;Xiong et al 2000;Gentil et al 2001;Brozzi et al 2009;Tsoporis et al 2009;Wen et al 2012;Agam and Almong 2015;Gogl et al 2016) and even interacts with the cytoskeleton (Baudier and Cole 1988;Donato 1988;Skripnikova and Gusev 1989;Mbele et al 2002), but data currently available do not appear to converge toward a clearly defined function. In contrast, there is mounting evidence indicating an increasingly clearer role for extracellular S100B.…”