Intermediate filaments as signaling determinants

Intermediate filaments (IFs) form structures that are essential for providing mechanical strength to cells. Interestingly, recent data point to an important function of IFs in cell signaling as scaffolding of critical signaling molecules. Our lab focuses on studying the signaling-mediated regulation of IFs as well as the role of IFs as signaling modulators in differentiation, cell stress and cancer.
Funding: Academy of Finland and Sigrid Jusélius Foundation

Current Projects

Post-translational modifications (PTMs) as regulators of IF structure and function

Post-translational modifications (PTMs) as regulators of IF structure and function

Post-translational modifications, in particular phosphorylation, are well known regulators of IF structure and function. We have several projects which aim to elucidate further the physiological roles of phosphorylation in the assembly, signaling, and cellular functions of vimentin, nestin, and lamin. These studies have already led to establishing the roles of a number of phosphorylation motifs, for example:

  • Vimentin PKC sites in migratory functions
  • Vimentin PKA sites in assembly
  • Nestin Cdk5 sites in survival and differentiation
  • Cdk sites in lamin assembly and functions

Our current studies focus on:

  • Characteristics of key vimentin phosphosites and their effect on vimentin organization and cellular functions such as proliferation, migration and invasion
  • Sphingolipid-mediated vimentin phosphorylation and cell motility
  • The role of phosphorylation in lamin A assembly and turn over as well as in lamin A mediated signaling

We have also successfully used the IFs as platforms for developing novel methods for phosphoproteomics, as they are abundant phosphoproteins that are subjected to a high phosphate turnover.

Vimentin as a signaling gatekeeper in injury

We propopse that vimentin, the type III cytoskeletal intermediate filament and a universal mesenchymal marker, may behave as a signaling scaffold in response to stress and upon injury. By collaboration with other intermediate filaments, for instance keratin upon the epithelium injury, nestin and desmin upon muscle injury and GFAP, nestin during the neuron damage, vimentin modify various cell fate and cellular activities and consequently lead to re-epithelialization, muscle regeneration or gliosis to maintain tissue integrity.

Our current research is focusing on vimentin’s role in epithelium injury under physiological and pathological conditions using a variety of in vitro and in vivo model systems.

IFs as regulators of cancer cell migration and invasion

We and others have shown that IFs are important for cell migration. An illustrative example of this function is the role of vimentin in the transcellular migration of lymphocytes. We are also pursuing the role of IFs in the migration of cancer cells. In cancer, the IFs are known primarily as markers of the degree of malignant transformation that a cancer cell has undergone. Keratin-expressing cells are believed to be un- or de-differentiated whereas vimentin expressing cells are understood to have undergone epithelial-mesenchymal transition (EMT) and have thus acquired a highly invasive and motile phenotype. Nestin, the binding partner of vimentin is expressed in a number of cancers including osteosarcoma, glioma and prostate cancer, although very little is known about its function in cancer. Several studies have suggested that nestin has a role in cancer cell motility.

Our current work indicates that nestin regulates the organization and activity of key migration mediators, the integrins, which has consequences for cell invasion.

Nestin-Cdk5 interplay in myogenesis and survival

Although nestin is a widely acknowledged neuronal stem cell marker, its expression is additionally induced in skeletal muscle tissue upon myoblast differentiation as well as injury. Moreover, nestin expression is specifically confined to neuromuscular- and myotendinous junctions in mature muscle. In a number of studies, we have established the function of a dynamic nestin scaffold as a regulator of bidirectional Cdk5 signaling in the context of neuronal apoptosis, muscle differentiation and neuromuscular junction maturation.

The present research project aims to elucidate further the roles and targets of both nestin and Cdk5 during muscle differentiation. By using the nestin KO mouse as a model, we are investigating the consequences of nestin ablation on muscle regeneration after injury.

Drosophila as a model to investigate intermediate filament evolution

Arthropods are unique among the animals in that they express no cytoplasmic intermediate filaments. We have transgenically expressed vimentin in Drosophila melanogaster. By studying the effect of the onset of vimentin expression we can learn about the fundamental function of this protein.

Responsible Team Members

  • Hend Abdelkader
  • Fang “Rose” Cheng
  • Josef Gullmets
  • Kimmo Isoniemi
  • Henok Karvonen
  • Julia Lindqvist
  • Ponnuswamy Mohanasundaram
  • Elin Torvaldson
  • Arun Venu
  • Meng Wang
  • Num Wistbacka