Integrin‐associated proteins as potential therapeutic targets

Abstract

Integrins are adhesion receptors important for hematopoiesis, leukocyte trafficking, and formation of immunological synapses; hence, they may provide targets for therapeutic intervention in leukocyte-driven pathologies. Blocking integrin-ligand binding is one strategy for inhibiting integrins; however, a complete loss of integrin function can lead to mechanism-based toxicities. Because integrin alpha and beta subunits interact with a variety of other proteins to receive and transmit cellular signals, targeting these integrin-associated proteins may utilize alternative sites for intervention that lead to therapies with fewer side effects. This review summarizes integrin-associated proteins in leukocytes and focuses on four of these proteins with perceived therapeutic potential. Specific mutations in the alpha4 integrin cytoplasmic tail block or enforce binding to paxillin and thus modulate integrin signaling required for efficient cell migration. Similarly, the association of RAPL(NORE1B) with beta2 integrins may participate in adhesive and migratory events in leukocytes. The beta integrin cytoplasmic tail-binding protein talin is critical for increasing the affinity of integrins (activation), and blockade of talin binding can prevent leukocyte arrest on the endothelium. Finally, the membrane protein CD98 mediates beta1 and beta3 integrin signaling and may be involved in leukocyte functions. Identification of biologically important interactions of integrins and signaling proteins can thus pave the way to new strategies for manipulating leukocyte functions.

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

“…Antagonists of α4 have shown promise in the treatment of autoimmune disorders such as multiple sclerosis and Crohn's disease, but the associated toxicities have led to the design of alternative approaches other than those directed at blocking integrin-ligand binding (40,41). Blocking α4 signaling may have important implications with respect to ablation of tumor vasculature, as it has been recently demonstrated that homing of progenitor cells to tumor areas undergoing active angiogenesis uses the α4 integrin/VCAM1 counter receptor pair (42,43).…”

2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy

“…However, actin also plays an important role in the 2B4-independent adhesion of NK cells to tumor target cells. The b 1 and b 2 integrins are linked to the actin cytoskeleton through talin, which has been shown to be essential for inside-out signaling (31). Additionally, LFA-1 in NK cells has the unique ability to transmit its own inside-out signal to other LFA-1 molecules (32).…”

Anti-metastatic effect of jolkinolide B and the mechanism of activity in breast cancer MDA-MB-231 cells

“…As a cell adhesion molecule, integrin participates in these cellular processes by mediating the adhesion of cells to the ECM and by transmitting signals that regulate these processes. Integrins are promising targets for the treatment of inflammatory and autoimmune diseases (3).…”