αvβ8 integrin adhesion and signaling pathways in development, physiology and disease

Abstract

Cells must interpret a complex milieu of extracellular cues to modulate intracellular signaling events linked to proliferation, differentiation, migration and other cellular processes. Integrins are heterodimeric transmembrane proteins that link the extracellular matrix (ECM) to the cytoskeleton and control intracellular signaling events. A great deal is known about the structural and functional properties for most integrins; however, the adhesion and signaling pathways controlled by αvβ8 integrin, which was discovered nearly 30 years ago, have only recently been characterized. αvβ8 integrin is a receptor for ECM-bound forms of latent transforming growth factor β (TGFβ) proteins and promotes the activation of TGFβ signaling pathways. Studies of the brain, lung and immune system reveal that the αvβ8 integrin-TGFβ axis mediates cell-cell contact and communication within complex multicellular structures. Perturbing components of this axis results in aberrant cell-cell adhesion and signaling leading to the initiation of various pathologies, including neurodegeneration, fibrosis and cancer. As discussed in this Review, understanding the functions for αvβ8 integrin, its ECM ligands and intracellular effector proteins is not only an important topic in cell biology, but may lead to new therapeutic strategies to treat human pathologies related to integrin dysfunction.

Keywords: Angiogenesis; Cancer; Extracellular matrix; Microenvironment; Pathophysiology.

Fig. 1.

Integrin αvβ8 regulates neurovascular development via activation of latent TGFβs. (A) Schematic illustration of the multicellular composition of a brain neurovascular unit, comprised of vascular endothelial cells and pericytes that are juxtaposed with astrocyte and microglial end feet. There are at least two basement membranes (highlighted by dark black lines) within the neurovascular unit, highlighting the importance of cell–ECM contact and communication in neurovascular biology. (B) αvβ8 integrin expressed in perivascular astroglial cells cooperates with microglial cell-expressed and secreted LRRC33 to bind to latent TGFβs embedded within the ECM. Interactions between integrin and LRRC33 induce structural rearrangements within the latent TGFβ complex, leading to paracrine activation of TGFβ receptor signaling in vascular endothelial cells. TGFβ receptor signaling via Smad transcription factors and other effectors leads to changes in gene expression programs that regulate angiogenesis during CNS development. Nrp1, which is expressed in brain endothelial cells, suppresses TGFβ signaling by serving as a counter-receptor for αvβ8 integrin, thereby blocking latent TGFβ activation. Genetic or pharmacological disruption of integrin engagement of TGFβ receptor signaling leads to severe CNS angiogenesis pathologies. The TGFβ receptor complex consists of a heterodimer of type 1 TGFβ receptor (indicated in red) and type 2 TGFβ receptor (indicated in black).

Fig. 2.

Integrin αvβ8 modulates cell–ECM adhesion and signaling events in the cancer microenvironment. αvβ8 integrin expressed in cancer cells (shown here is an example of the brain cancer GBM) mediates the activation of ECM-bound latent TGFβs in the tumor microenvironment. Active TGFβ subsequently engages with its receptors to coordinately activate paracrine angiogenic pathways in vascular endothelial cells and suppress T cell activation. In addition, TGFβ signaling in cancer cells activates intracellular signaling pathways involving PTP-PEST, RhoGDI1 and other effectors that promote growth and invasion in the tissue microenvironment.

Fig. 3.

A summary of intracellular signaling pathways regulated by αvβ8 integrin. The cytoplasmic domain of β8 integrin can bind to various intracellular signaling effectors, including the non-receptor protein tyrosine phosphatase PTP-PEST, which subsequently regulates p130Cas activities in focal adhesions and VCP/p97 in the ubiquitin proteasome system. β8 integrin also binds directly to the Rho GTPase regulatory factor RhoGDI1, which controls the activation states of Rac1 and Cdc42 GTPase. Finally, the β8 integrin cytoplasmic domain can link to the actin cytoskeleton through interactions with Band 4.1 proteins.