Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments

Abstract

Phosphorylation of types III and IV intermediate filaments (IFs) is known to regulate their organization and function. Phosphorylation of the amino-terminal head domain sites on types III and IV IF proteins plays a key role in the assembly/disassembly of IF subunits into 10 nm filaments, and influences the phosphorylation of sites on the carboxyl-terminal tail domain. These phosphorylation events are largely under the control of second messenger-dependent protein kinases and provide the cells a mechanism to reorganize the IFs in response to the changes in second messenger levels. In mitotic cells, Cdk1, Rho kinase, PAK1 and Aurora-B kinase are believed to regulate vimentin and glial fibrillary acidic protein phosphorylation in a spatio-temporal manner. In neurons, the carboxyl-terminal tail domains of the NF-M and NF-H subunits of heteropolymeric neurofilaments (NFs) are highly phosphorylated by proline-directed protein kinases. The phosphorylation of carboxyl-terminal tail domains of NFs has been suspected to play roles in forming cross-bridges between NFs and microtubules, slowing axonal transport and promoting their integration into cytoskeleton lattice and, in doing so, to control axonal caliber and stabilize the axon. The role of IF phosphorylation in disease pathobiology is discussed.

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

“…Association of vimentin phosphorylation and disassembly of its filament network has been detected in vitro and in different cell types including epithelial as well as mesenchymal cells [15,33]. These phosphorylation events are thought to mainly involve the vimentin N-terminal serine residues [15,26,40] and, in agreement, our data showed a major effect of PI3Kg signaling on Ser6 phosphorylation.…”

“…These phosphorylation events are triggered by a wide range of protein kinases, such as PKA and PKC [15,19], PKG [20], Rho-kinase and Aurora B [21], PAK [22,23], MAPKAP K-2 [10], Cdc2 kinase [24] and CaMKII [25] and involve a large number of serine residues (e.g. Ser 4,[6][7][8][9]25,33,38,41,50,55,65,71,72,82) with a complex pattern of overlapping specificities [15,26,27].…”

“…These phosphorylation events are triggered by a wide range of protein kinases, such as PKA and PKC [15,19] [25] and involve a large number of serine residues (e.g. Ser 4,[6][7][8][9]25,33,38,41, 50, 55, 65, 71, 72, 82) with a complex pattern of overlapping specificities [15,26,27].Although vimentin appears involved in multiple cellular processes, mice lacking this protein are viable and do not show overt phenotypes [28]. Nonetheless, fibroblasts from vimentindeficient mice show mechanical instability and impaired ability to migrate and to contract a 3-D collagen network [29], thus providing a genetic evidence for the involvement of vimentin in cell plasticity and motility [30,31].…”

“…Similar results were also obtained with PI3Kg KD/KD BMDM ( Fig. 4D), thus demonstrating the involvement of PI3Kg catalytic activity in the process leading to vimentin serine phosphorylation.Chemokines stimulate PI3Kc-dependent vimentin structure disassemblyAs N-terminal serine phosphorylation of vimentin is responsible for vimentin fiber disassembly and cytoskeletal remodeling [27,30,33], the effects of the lack of PI3Kg on vimentin polymerization dynamics were investigated by immunofluorescence. Disassembly of vimentin filaments was evident, in WT BMDM, 5 min after stimulation with CCL5 (Fig.…”

Intermediate filaments: versatile building blocks of cell structure

“…At higher protein concentrations under more physiological conditions, the rate of elongation is faster (H. Herrmann, personal communication). Assembly in vivo is most likely to be much faster, since IF protein concentration is higher (~2-3% of total fibroblast protein, unpublished observations) and physiological conditions are optimal (e.g., the extent of phosphorylation [15,16]). Once longer IF are formed, there is a "radial compaction" phase in which molecular re-arrangements result in a decrease in filament diameter from ~17 nm to the mature dimension of 10 nm [17].…”