Insights into intermediate filament regulation from development to ageing

Abstract

SummaryIntermediate filament (IF) proteins comprise a large family with more than 70 members. Initially, IFs were assumed to provide only structural reinforcement for the cell. However, IFs are now known to be dynamic structures that are involved in a wide range of cellular processes during all stages of life, from development to ageing, and during homeostasis and stress. This Commentary discusses some lesser-known functional and regulatory aspects of IFs. We specifically address the emerging roles of nestin in myogenesis and cancer cell migration, and examine exciting evidence on the regulation of nestin and lamin A by the notch signalling pathway, which could have repercussions for our understanding of the roles of IF proteins in development and ageing. In addition, we discuss the modulation of the post-translational modifications of neuronally expressed IFs and their protein-protein interactions, as well as IF glycosylation, which not only has a role in stress and ageing, but might also regulate IFs during development. Although many of these recent findings are still preliminary, they nevertheless open new doors to explore the functionality of the IF family of proteins. Journal of Cell ScienceCdk5 is associated with nestin in myoblasts, neuronal precursor cells (Sahlgren et al., 2003) and human podocytes (Bertelli et al., 2007). Cdk5 phosphorylates nestin, and this phosphorylation regulates the organization of nestin filaments (Box 2) during myogenic differentiation (Sahlgren et al., 2003). Interestingly, the interaction between nestin and Cdk5 is not limited to a typical kinase-substrate relationship. In neuronal precursor cells, nestin forms a scaffold for Cdk5 and the Cdk5 activator p35, thereby sequestering them to the cytoplasm, which consequently inhibits the proapoptotic function of Cdk5 during oxidative stress (Sahlgren et al., 2006). In turn, it has recently been demonstrated that Cdk5 is targeted by protein kinase C- (PKC) during myogenesis (de Thonel et al., 2010). PKC is essential for proper myoblast differentiation. It targets Cdk5 by phosphorylating p35 at a site that triggers the activation of calpains, which then cleave p35 into p25. The cleavage of p35 into p25 creates a more stable protein fragment, and this fragment is capable of sustained Cdk5 activation, consequently promoting nestin reorganization (Fig. 1,. An earlier study, in cultured neurons, demonstrated that Cdk5 is also able to regulate p35 by phosphorylation, thereby protecting it from calpain-mediated cleavage (Kamei et al., 2007). Furthermore, a recent study has shown that nestin has the capacity to modulate Cdk5-mediated differentiation and terminal organization of muscle cells (Pallari et al., 2011) (Fig. 1, left-hand side). Taken together, these results suggest that a balance between Cdk5 and PKC is important for proper myogenic differentiation, as they show that disturbance of the PKC-Cdk5-nestin signalling pathway leads to nestin reorganization and impedes myoblast differentiation, implying that nestin also plays a k...

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…The view that vimentin potentiates Jagged function is corroborated by the data showing that Jagged expression correlates with vimentin expression in several tissues and in cancer, in particular. Elevated expression of both vimentin and Jagged has been implicated in tumor progression (6,8,10,16,(73)(74)(75)(76). Furthermore, observations in vimentin knockout mice links vimentin to defects in wound healing, fibrosis, inflammation, epidermal aging, and epithelial mesenchymal transition in cancer (4,7,8).…”

“…Whereas IFs provide cells with mechanical stability, there is mounting evidence indicating that IFs are involved in a range of metabolic, signaling, and regulatory processes that are unrelated to mechanical functions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The vimentin IF has been shown to act as a scaffold for signaling proteins that regulate epithelial mesenchymal transition (EMT), cancer cell invasion, wound healing and tissue repair, tissue aging, as well as inflammatory signaling (3,4,(6)(7)(8)10).…”

Sphingolipids inhibit vimentin-dependent cell migration

“…In light of our results, we suggest that pS71-vimentin is important for chemotaxis. This might be because vimentin is important for cell motility, with a role in organising receptor molecules on the cell membrane and in the cellular localisation of adhesion-associated molecules and migration-regulating kinases (Hyder et al, 2011;Nieminen et al, 2006;Pallari and Eriksson, 2006;Sin et al, 1998). The exact role of vimentin phosphorylation in these processes remains to be determined.…”

“…Another member of the intermediate filament family, vimentin, has well established roles in migratory signalling and processes, often acting in concert with K8/K18 (Hyder et al, 2011;Ivaska et al, 2007;Pallari and Eriksson, 2006). Interestingly, an early study indicated that S1P caused vimentin filament reorganisation (Sin et al, 1998).…”

Phosphorylation of lamins determine their structural properties and signaling functions

“…1 The IFs share a common structure consisting of a structurally conserved rod domain flanked by variable head and tail regions. 2 Except for the lamins all IFs are cytoplasmic proteins that are part of the cytoskeleton.…”