Spectraplakin family proteins - cytoskeletal crosslinkers with versatile roles

Abstract

The different cytoskeletal networks in a cell are responsible for many fundamental cellular processes. Current studies have shown that spectraplakins, cytoskeletal crosslinkers that combine features of both the spectrin and plakin families of crosslinkers, have a critical role in integrating these different cytoskeletal networks. Spectraplakin genes give rise to a variety of isoforms that have distinct functions. Importantly, all spectraplakin isoforms are uniquely able to associate with all three elements of the cytoskeleton, namely, F-actin, microtubules and intermediate filaments. In this Review, we will highlight recent studies that have unraveled their function in a wide range of different processes, from regulating cell adhesion in skin keratinocytes to neuronal cell migration. Taken together, this work has revealed a diverse and indispensable role for orchestrating the function of different cytoskeletal elements in vivo.

Keywords: Cell–cell junction; Cell–matrix adhesion; Cytoskeletal coordination; F-actin; Intermediate filament; Microtubule; Spectraplakin.

Fig. 1.

Isoforms and domain structures of mammalian and invertebrate spectraplakins. (A) Major isoforms of the spectraplakin proteins MACF1, BPAG1, Shot, VAB-10 and MACF1a are classified according to their domain structure similarity. Many functional domains can be identified in spectraplakin family proteins, including: calponin homology (CH) domains for F-actin binding, a plakin domain, an α-helical spectrin repeat domain, a PRD, plectin repeats, tandem EF-hand motifs (the distal and proximal motif to the GAR domain are differentially colored), and a GAS2-related (GAR) domain for MT interaction. The number of spectrin repeats and plectin repeats are descriptive in nature and may vary in different spectraplakins. The figure is not drawn to scale with respect to the actual spectraplakin proteins. This panel has been adapted from Suozzi et al. (2012) with permission. (B) The similarity of the spectraplakin members. The homology tree was generated using MAFFT version 5 with annotated sequences of spectraplakin proteins retrieved from NCBI genebank database (accession numbers given in parenthesis) (Katoh et al., 2005).

Fig. 2.

Molecular mechanisms of spectraplakin regulation. (A) The Drosophila spectraplakin Shot is regulated by intramolecular inhibition. An intramolecular auto-inhibitory interaction occurs between the N-terminal actin-binding domains (ABDs) and the C-terminal MT-binding GAR domain. In response to activating signals at the cell cortex, this intramolecular inhibitory interaction is disrupted and Shot is able to crosslink cytoskeletal networks by binding to both MTs and F-actin. (B) The cytoskeletal crosslinking activity of mammalian spectraplakins can be regulated by protein phosphorylation. Tyrosine phosphorylation (P) at the N-terminal F-actin-binding domain of MACF1 can enhance its association with F-actin, and promote focal adhesion dynamics in cultured skin keratinocytes. In addition, phosphorylation of its C-terminal MT-binding domain by GSK3 kinase can disrupt its interaction with MTs. Ca²⁺ can also regulate BPAG1n4 through its C-terminal EF-hand motifs. An increase in Ca²⁺ can lead to a rapid switching between the MT-plus-end and lattice-binding of the C-terminal domain of BPAG1n4. (C) The spectraplakin MACF1 interacts with CAMSAP3 at the minus end of noncentrosomal MTs and anchors them to actin filaments.

Fig. 3.

Localization and cellular function of spectraplakins. Spectraplakins orchestrate various cytoskeletal interactions and mediate crosslinking in different cellular compartments. Therefore, they are able to regulate different cellular processes as illustrated here. 1, spectraplakins mediate the MT targeting of MTs to focal adhesions, which promotes focal adhesion turnover and cell motility; 2, spectraplakins have been shown to regulate the integrity of the nucleus, ER and the Golgi complex, as well as and vesicle transport; 3, spectraplakins also associate with adaptors such as ELMO proteins and mediate cytoskeletal crosslinking at the cortical membrane; 4, spectraplakins connect hemidesmosomes with IFs and strengthen the integrity of the basal layer.