Regulation and functions of integrin α2 in cell adhesion and disease

Abstract

Integrins are cell adhesion molecules that are composed of an alpha (α) subunit and a beta (β) subunit with affinity for different extracellular membrane components. The integrin family includes 24 known members that actively regulate cellular growth, differentiation, and apoptosis. Each integrin heterodimer has a particular function in defined contexts as well as some partially overlapping features with other members in the family. As many reviews have covered the general integrin family in molecular and cellular studies in life science, this review will focus on the specific regulation, function, and signaling of integrin α2 subunit (CD49b, VLA-2; encoded by the gene ITGA2) in partnership with β1 (CD29) subunit in normal and cancer cells. Its roles in cell adhesion, cell motility, angiogenesis, stemness, and immune/blood cell regulations are discussed. The pivotal role of integrin α2 in many diseases such as cancer suggests its potential to be used as a novel therapeutic target.

Keywords: CD49b; Integrin α2; Molecular mechanisms; Regulation; Signaling.

Figure 1

Loci of genes encoding integrin α1 (ITGA1) and α2 (ITGA2) in the human chromosome. ITGA1 is around 170 kb in length while ITGA2 is 110 kb in length. Adapted from Kulich, et al 2002.

Figure 2

Protein model of integrin α2 domain I binding to collagen. The crystal that was used for determination of the structure grew in Co²⁺ ion, which supports collagen adhesion in vitro. The domain I is circled.

Figure 3

Canonical pathway for α2β1 signaling. Upon collagen or laminin binding to integrin α2β1, a series of signaling events occur to promote survival, proliferation, migration, and invasion. Integrins are often recycled to provide a refreshed pool of integrins to the surface membrane.

Figure 4

Roles of integrin α2β1 in multiple types of cancer. Top panel: Melanoma cells that produce high levels of VEGF and PLGF can stimulate endothelial cells of α2-null mice, which have increased VEGFR1 to stimulate angiogenesis. Right panel: Ovarian cancer cells that express high levels of EGFR can block integrin α2β1 signaling by increasing its internalization. Left panel: In prostate cancer, α2β1 promotes invasion by RhoC GTPase expression. Bottom panel: Absence of α2β1 in the stroma of host mice promotes spontaneous metastasis of transgenic c-neu oncogene-initiated breast cancer.