Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton

Abstract

It has become widely accepted that adhesion receptors can either directly activate, or significantly modulate, many of the signaling cascades initiated by circulating growth factors. An interesting recent development is the realization that adhesion receptors and their cytoskeletal partners can regulate the trafficking of signaling proteins between the cytoplasm and nucleus. Cell adhesion molecule control of nucleocytoplasmic trafficking allows adhesion to influence many cell decisions, and highlights the diversity of nuclear import and export mechanisms.

Figure 1.

Adhesion regulation of nucleocytoplasmic trafficking of signaling molecules. CAMs regulate the nucleocytoplasmic trafficking by several mechanisms. Firstly, cadherins, β2 integrins, and syndecans directly act as cytoplasmic anchors for β-catenin, JAB1, and CASK, respectively. Nuclear accumulation of β-catenin may also be regulated by the integrin-linked kinase pathway. In the nucleus, β-catenin interacts with the TCF family member LEF-1 to regulate expression of genes, such as c-Myc and cyclin D1. JAB1 interacts with c-Jun containing AP-1 complexes, and enhances transactivation from AP-1–dependent promoters. CASK binds DNA in a complex with Tbr-1 to induce transcription of genes important in cerebrocortical development. Second, protein complexes associated with sites of adhesion act as sinks for a variety of proteins, for example zyxin, that contain LIM domains and traffic to the nucleus. Additionally, integrin-mediated adhesion and an intact actin cytoskeleton are important in controlling efficient ERK nucleocytoplasmic trafficking and phosphorylation of downstream transcription factors.