Intermediate filaments in smooth muscle

Abstract

The intermediate filament (IF) network is one of the three cytoskeletal systems in smooth muscle. The type III IF proteins vimentin and desmin are major constituents of the network in smooth muscle cells and tissues. Lack of vimentin or desmin impairs contractile ability of various smooth muscle preparations, implying their important role for smooth muscle force development. The IF framework has long been viewed as a fixed cytostructure that solely provides mechanical integrity for the cell. However, recent studies suggest that the IF cytoskeleton is dynamic in mammalian cells in response to various external stimulation. In this review, the structure and biological properties of IF proteins in smooth muscle are summarized. The role of IF proteins in the modulation of smooth muscle force development and redistribution/translocation of signaling partners (such as p130 Crk-associated substrate, CAS) is depicted. This review also summarizes our latest understanding on how the IF network may be regulated in smooth muscle.

Figure 1. Molecular structure of vimentin in smooth muscle

The structure of vimentin consists of a central rod domain, an N-terminal “head” domain, and a C-terminal “tail” domain. These domains are separated by 3 linkers referred to as L1, L12 and L2. Two monomers pair to form a parallel coiled-coil dimer. A pair of dimers associates laterally into an antiparallel tetramer, a soluble subunit for IF assembly in cells. Ser-56 is a major phosphorylation site on vimentin in smooth muscle in response to contractile stimulation. Desmin shares similar molecular structure and assembly processes.

Figure 2. Proposed role and regulation of the vimentin network in smooth muscle

Contractile agonists activate the protein kinase PAK, which mediates vimentin phosphorylation at Ser-56. Vimentin phosphorylation may lead to the spatial reorientation and partial disassembly of vimentin filaments. The spatial remodeling of the vimentin cytoskeleton may induce the structural reorganization of contractile elements and/or desmosomes. CAS and CamKII may dissociate from cytoskeletal vimentin. The released CAS may promote cortical actin polymerization in smooth muscle. In addition, the released CAS may render PAK active via the multiprotein complex. The activated CamKII may regulate MAPK that has been shown to mediate caldesmon phosphorylation. These structural and signaling changes in smooth muscle may facilitate active force development in response to contractile stimulation. Green line represents vimentin filaments (VFs); red circle, CAS; blue circle, CamKII; Sol Vim, soluble vimentin.