Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101951



Historical Background

Intermediate filaments (IF) are a family of proteins that are an important cytoskeletal component. Vimentin is a Type III intermediate filament that is primarily found in mesenchymal cells. Initially, it was assumed that the IFs served purely as a structural entity to give cells their shape and maintain their integrity. Over the past two decades, numerous roles and functions of the vimentin protein have been uncovered such as cellular migration, adhesion, and signaling. Historically, vimentin has been used as a tumor marker (Kidd et al. 2014). Moreover, recent research has uncovered that the IF protein is involved in numerous aspects of cancer development such as metastasis and the epithelial-mesenchymal transition (EMT) (Mendez et al. 2010). Additionally, it has become clear in recent years that vimentin may also play a role in several other pathologies such as colitis (Mor-Vaknin et al. 2013), Crohn’s disease (Henderson et al. 2012), and development of cataracts (Muller et al. 2009).


The 57 kD cytoskeletal protein is encoded by a sequence that is highly conserved across species (Perreau et al. 1988) and is expressed in mesenchymal cells such as endothelial cells, macrophages, neutrophils, and fibroblasts. As a member of the larger IF family, vimentin, like all intermediate filaments has low solubility and forms a tripartite structure that consists of an alpha-helical rod domain which is capped by nonhelical head and tail domains, at the N- and C-termini, respectively (Fig. 1a) (Chernyatina et al. 2012), and it is these monomers that form dimers, staggered antiparallel tetramers, oligomers, and ultimately the distinct 10 nm filaments (Fig. 1b). Mutagenesis studies demonstrated that the N-terminal head domain is important for vimentin filament formation as a mutant “headless” vimentin construct displayed an inability to form filaments (Herrmann et al. 1996).
Vimentin, Fig. 1

Schematic of vimentin structure and filament assembly. (a) Each vimentin monomer consists of a central alpha-helical rod domain, an N-terminal head domain, and a C-terminal tail domain. (b) Vimentin filament assembly starts by the dimerization of two monomers. These dimers then form a staggered antiparallel tetramer, which then form larger oligomers, ultimately giving rise to the characteristic 10 nm vimentin filament. Boxed area represents the filament cross-section highlighting the antiparallel tetramers

Vimentin is posttranslationally modified in its amino acid sequence, many of these modifications being phosphorylation of serine residues. Due to the nature of the central alpha-helical rod domain, most phosphorylation sites are located in the head and tail domains. As shown in Table 1, these serine residues are phosphorylated by several classes of kinases. The phosphorylation of specific amino acids regulates the assembly and disassembly of the vimentin filament network, which plays an important role in a variety of cellular functions.
Vimentin, Table 1

Vimentin phosphorylation sites and the associated functions and kinases


Amino acid residue(s)


Protein Kinase A (PKA)

Ser6, Ser24, Ser28, Ser38, Ser46, Ser50, Ser65, Ser72

(Eriksson et al. 2004)

Protein Kinase C (PKC)

Ser6, Ser8, Ser9, Ser20, Ser24, Ser25, Ser28, Ser33, Ser38, Ser41, Ser50, Ser65

(Goto et al. 1998; Ivaska et al. 2005)

CaM kinase II (CamKII)

Ser38, Ser82

(Goto et al. 1998)

p21-activated kinase (PAK)

Ser25, Ser38, Ser50, Ser65, Ser72

(Li et al. 2006)


Ser41, Ser55

(Yamaguchi et al. 2005)

Rho-kinase (RhoK)

Ser38, Ser71

(Goto et al. 1998)



(Yamaguchi et al. 2005)

Aurora-B kinase

Ser6, Ser24, Ser38, Ser46, Ser64, Ser65, Ser72, Ser86

(Goto et al. 2003)



(Zhu et al. 2011)


Structural Integrity

The intracellular vimentin network plays an important role in maintaining cytoskeletal integrity allowing cells to maintain their shape (Nieminen et al. 2006; Mendez et al. 2010) and provide protection from stress (Mendez et al. 2014; Perez-Sala et al. 2015). Vimentin also is of great importance for intracellular organelle placement and movement. For example, live cell imaging studies in which the vimentin network was disrupted demonstrated altered cellular distribution and motility of mitochondria (Nekrasova et al. 2011).

Moreover, in addition to providing mitochondria with structural support, vimentin also plays a role in mitochondrial membrane potential regulation (Chernoivanenko et al. 2015).


The vimentin filament network not only is involved in the movement and motility of intracellular components but also plays a key role in the motility and migration of the cell itself, processes driven by the constant disassembly and reassembly of the network. An important cellular process that requires proper cell migration is wound healing. Studies using scratch wound assays demonstrated that increased vimentin protein expression led to faster wound closure, and that this increased expression was induced by TGFß1, a key cytokine in acute lung injury (ALI) (Rogel et al. 2011; Cheng et al. 2016). Studies using fibroblasts from vimentin-null mice further stressed the importance of vimentin in wound healing, showing that these cells had an impaired ability to migrate, leading to delayed wound healing in (Eckes et al. 2000). In addition to cell migration involved in wound healing, vimentin also regulates lymphocyte adhesion lymphocyte endothelial transmigration (Nieminen et al. 2006).

As was previously mentioned, vimentin is a well-known marker of EMT, a process characterized by increased cell migration due to loss of cell-cell adhesions and subsequent increased cellular mobility and migration. Specifically, as epithelial cells undergo EMT and transition from an epithelial to mesenchymal phenotype, they show a significant increase in expression of the IF protein, making vimentin a classic EMT marker. Furthermore, migration and metastasis of these transformed cells is driven by the dynamic vimentin network (Kidd et al. 2014).


Integrins are a family of transmembrane receptors that play an important role in cell adhesion and cell signaling with its surroundings. Due to their transmembrane structure, the integrins have both intra- and extra-cellular domains, and it has been shown that the intracellular cytoplasmic domain interacts with vimentin in endothelial cells and that this interaction plays a role in influencing the integrin-mediated cell-cell interactions. Moreover, studies on angiogenic sprouting have demonstrated that vimentin is necessary for focal adhesion (FA) organization (Ivaska et al. 2007).

Cell Proliferation and Apoptosis

Disassembly and reassembly of the vimentin network play an important role in mitosis. This rapid and coordinated process is driven by phosphorylation of vimentin by various kinases such as Aurora-B, Cdk-1, and Rho-kinase (see Table 1). Moreover, vimentin also is involved in apoptosis, as studies have shown that specific cleavage of vimentin promotes cell death (Byun et al. 2001), and mutation studies demonstrated the importance of vimentin in apoptosis control, as point mutations delayed cell death (Schietke et al. 2006).

Vimentin Dynamics

It was discovered almost 50 years ago that the distribution of the vimentin network in the cell is tied to microtubule dynamics, when studies revealed that depolymerization of microtubules using colchicine led to retraction of the vimentin filament network (Goldman 1971). The importance of the microtubule network was further supported when inhibition of kinesin and dynein, two microtubule-based motor proteins, altered the vimentin network (Gyoeva and Gelfand 1991).

Studies using GFP-coupled vimentin demonstrated that vimentin foci translocate rapidly in a cell and that this motility is governed by lengthening and shortening of the vimentin filaments. This motility has been shown to be largely governed by vimentin’s interactions with the microtubule network in the cell (Hookway et al. 2015; Robert et al. 2015) (Table 2).
Vimentin, Table 2

Summary of vimentin involvement in numerous biological processes





Structural integrity

Focal adhesions and cell junctions

Interactions with extracellular matrix

Maintenance and modulation of cell shape, overall tissue integrity, wound repair

(Mendez et al. 2010; Rogel et al. 2011)

Migration and adhesion

Adhesion molecules, cytoskeletal proteins, integrins

Assembly and disassembly of adhesion complexes

(Ivaska et al. 2007; Mendez et al. 2010)

Cell proliferation and apoptosis

Apoptosis and autophagy regulators

Genomic DNA

Mitotic spindle

Alteration of cell death and autophagy by complex formation and sequestration, mitosis

(Yamaguchi et al. 2005; Wang et al. 2012; Kidd et al. 2014; Cheng et al. 2016)

Immune defense

NLRP3 inflammasome, NOD2, viral components,


Activation of innate immune system, lymphocyte transmigration

(Nieminen et al. 2006; Stevens et al. 2013; dos Santos et al. 2015)


Beclin-1, 14-3-3, Protein kinases, receptors, transcription factors

Kinase mobilization, receptor localization, complex formation to promote activity

(Eriksson et al. 2004; Zhu et al. 2011; Kidd et al. 2014)


In addition to its intracellular structure, adhesion, and motility functions, the extensive vimentin network also acts as a dynamic scaffold for various signaling components by controlling their physical location within the cells, as well as guiding and relocating signaling molecules to their targets (Sin et al. 1998). Vimentin therefore is of great importance for cytoskeletal signaling pathways and cellular cross talk (Chang and Goldman 2004). This role is regulated by posttranslational modifications (PTMs), such as phosphorylation (Table 1), which induce the dynamic rearrangement of the vimentin filament network. The quick disassembly and reassembly of the vimentin network is required for successful mitosis, a process which is initiated by the phosphorylation of Ser55 by Cdk-1 (Li et al. 2006) and followed by the phosphorylation of Ser82 by Plk-1 and of Ser72 by Aurora-B kinase. Moreover, phosphorylation of Ser71 by Rho kinase (RhoK) is involved in the regulation of cytokinesis (Goto et al. 1998). PKA and PKC are two further kinases that are able to phosphorylate serine-residues in the head domain of vimentin (Eriksson et al. 2004) and affect filament polymerization.

Aside from the PTMs associated with normal cellular functions, there are also numerous phosphorylations involving vimentin that are associated with pathologies, most notably cancer development, and many studies have demonstrated that vimentin is involved in pathways involved in tumor growth and metastasis. One such pathway is the PI3K/Akt pathway, an important regulatory pathway which is upregulated in various types of cancer. One of its key players, the Akt1 kinase, binds vimentin and phosphorylates the protein at Ser39. This phosphorylation leads to vimentin being protected from proteolysis and results in increased cell motility and invasiveness in vitro. In vivo data confirmed that vimentin phosphorylation enhanced metastatic growth (Zhu et al. 2011). Another hallmark of cancer development is the inability of cells to undergo autophagy, thus promoting the survival of aberrant cells. It was shown that Beclin 1, a tumor suppressor protein normally involved in autophagy regulation, is phosphorylated by Akt leading to enhanced binding to both 14-3-3 and vimentin, and it is thought that this binding interaction leads to the inhibition of autophagy (Wang et al. 2012).

Several other studies have further underlined the role of vimentin in key steps of oncogenesis such as EMT, which is the process by which cells lose their epithelial phenotype and gain a mesenchymal phenotype. This transition is characterized by a significant change in cell shape and motility, a loss of polarity and a significant increase in vimentin expression, thus making vimentin a well-known marker of EMT. One study demonstrated that the vimentin intracellular network brings Slug and ERK into close proximity, leading to the phosphorylation of Slug, which is considered to be a key step in EMT (Virtakoivu et al. 2015). Moreover, during EMT, vimentin binds to Scrib, a protein necessary for migration, which prevents its degradation thus further stimulating cell invasiveness (Kidd et al. 2014).

Interestingly, it was recently demonstrated that vimentin plays an important role in the regulation and activation of the NLRP3 inflammasome (dos Santos et al. 2015), a structure shown to play a central role in inflammation and fibrosis during acute lung injury (ALI). Using in vivo mouse models of ALI, the authors demonstrated that vimentin and NLRP3 physically interacted and that this physical interaction was required for the activation of the inflammasome. More importantly, their findings showed that a lack of the vimentin protein in their vimentin-null mice led to a less severe disease phenotype and lower levels of inflammatory cytokines and mediators. Moreover, the vimentin deficiency in these mice reduced tissue injury and fibrosis.

In addition to its interaction with NLRP3, vimentin was found to interact with another innate immune response protein, namely the nucleotide oligomerization domain protein 2 (NOD2), a receptor for bacterial cell wall component MDP that activates downstream processes such as NF-kB activation and autophagy. Specifically, it was shown that vimentin interacts with NOD2 and regulates its activity (Stevens et al. 2013).

Taken together, these findings suggest that vimentin could play an important role in the control of several innate immune response pathways.

Future Directions

While numerous interactors of vimentin were described, uncovering new interactions of the vimentin filament network will help us gain a further understanding of the breadth of its impact and importance in the control of other cellular processes. Moreover, it will be of great interest to elucidate where vimentin and its binding partners, e.g., NLRP3, bind. With regards to its role in cancer metastasis, it remains unclear exactly how changes in vimentin expression change metastatic potential of the cell. Additionally, the fact that vimentin has been shown to modulate mitochondrial motility as well as membrane potential begs the question just how much vimentin controls the organelles response to outside stressors such as reactive oxygen species (ROS).


This chapter has illustrated the importance of vimentin in many physiological processes including cell migration and adhesion, inflammation, EMT, wound repair, and signaling. Furthermore, the fact that vimentin is phosphorylated by a variety of protein kinases was highlighted using examples of some the key targets of these posttranslational modifications. It is clear that the vimentin filament network is no longer viewed as a merely static entity, but is a highly dynamic network of filaments and that its role goes far beyond providing cells with structural support.

See Also


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical CareNorthwestern UniversityChicagoUSA