Integrin cytoplasmic tail interactions

Abstract

Integrins are heterodimeric cell surface adhesion receptors essential for multicellular life. They connect cells to the extracellular environment and transduce chemical and mechanical signals to and from the cell. Intracellular proteins that bind the integrin cytoplasmic tail regulate integrin engagement of extracellular ligands as well as integrin localization and trafficking. Cytoplasmic integrin-binding proteins also function downstream of integrins, mediating links to the cytoskeleton and to signaling cascades that impact cell motility, growth, and survival. Here, we review key integrin-interacting proteins and their roles in regulating integrin activity, localization, and signaling.

Figure 1

Direct integrin cytoplasmic tail interactors. Interactions between integrin cytoplasmic tails and intracellular proteins regulate integrin activity, surface expression, and downstream signaling. Here we depict known direct integrin interactors, their sites of interaction on α- or β-tails, and their functional role by color, as indicated in the legend. Conserved tail residues are displayed in uppercase letters; highly conserved residues are shown in bold.

Figure 2

Regulation of integrin activation. Integrin activation may be regulated by post-translational modifications of the tail (e.g., phosphorylation) and through competition between activators and inhibitors for binding the β-tail. Inhibitors of integrin activation may be competed off integrin tails by other intracellular proteins (e.g., migfilin–filamin and Krit1–ICAP1 binding).

Figure 3

Integrin interactors involved in sorting and surface expression. Integrin surface expression is carefully regulated by clathrin-dependent and -independent endocytosis, short-loop Rab4-dependent sorting, and long-loop Rab11-dependent sorting. Direct integrin interactors have been implicated as regulators throughout these pathways, as indicated by thick rectangular outlines.

Figure 4

Integrin–cytoskeletal connections. The dynamic connection between integrins and the cytoskeleton is mediated by a host of adhesion proteins. Here, we show how integrin-binding proteins contribute to the integrin–cytoskeletal connection to orchestrate directed migration.

Figure 5

Integrin interactions and downstream signaling. In the top panel, β-integrin interactions are highly interconnected and play important roles when signaling to the cytoskeleton. Orange proteins indicate direct actin binders. In the bottom panel, many integrin-binding proteins impact the spatial and temporal regulation of Rho family GTPases to affect cytoskeletal organization.