Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

Abstract

The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27. As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases will be presented.

Fig. 1

Structural properties of human Hsp27. a Schematic diagram of human Hsp27 showing the WDPF domain, the conserved N-terminal region, and the α-crystallin domain. The zigzag line corresponds to the flexible domain in the C-terminal part of the protein. The numbers refer to the amino acid residues. The phosphorylation sites Ser-15, Ser-78, and Ser-82 are indicated. The protein kinases shown to phosphorylate Hsp27 at these sites in vivo are indicated in black, while the protein kinases that were reported to phosphorylate these sites in vitro are depicted in red. b Alignment of the amino acid sequences of human (h) and rat (r) heat shock protein 27, and the mouse (m) homologue Hsp25. *Indicates an identical corresponding residue. The phosphoacceptor sites Ser-15, Ser-78, and Ser-82 (resp. Ser-86) are shown in red boxes. The one-letter amino acid code is used. c Comparison of the regions encompassing the phosphoacceptor sitesSer-15, Ser-78, and Ser-82 in human Hsp27 with the corresponding regions in Hsp27 homologous of other animals

Fig. 2

Schematic presentation of the functions linked to phosphorylated Hsp27. Top panel Under normal conditions, phosphorylated Hsp27 exerts anti-proliferative and anti-apoptotic effects, and is involved in platelet granule secretion and actin filament dynamics. Bottom panel Anomalous Hsp27 phosphorylation levels (indicated by the triangle) has been correlated to pathologies such as viral infections, specific tumor cells, autoimmune diseases of the skin (pemphigius vulgaris and pemphigius foliaceus, kidney diseases (e.g., epithelial-to-mesenchymal transition; EMT), and increased lipoprotein lipase (LPL) secretion in diabetic cardiomyocytes. See text for details