In mammals, integrins are membrane receptors composed of 18 α-subunits and 8 β-subunits, which pair to produce a total of 24 different combinations of integrin molecules.These proteins have a large extracellular domain and a short cytoplasmic tail linked by a transmembrane region.
The extracellular domains of the α and β dimers link to proteins present on the extracellular matrix or receptors in other cells. The cytoplasmic tails bind to the cytoskeleton. Therefore, integrins provide an avenue for the cell to sense and respond to its environment (Alberts et al., 2002).
Activation of integrin occurs from inside the cell, called inside-out signaling, and involves binding the cytoplasmic tail to the protein talin and destabilizing the connection to the transmembrane region. This causes the ligand-binding headpiece in the extracellular domain to adapt an upright position, priming the integrin to bind to a ligand.
Once bound, this ligand-binding headpiece returns to a stabilized position, instigating the separation of the subunits composing the transmembrane region and cytoplasmic tail. This in turn allows the initiation of several signaling pathways, by recruiting intracellular molecules to bind to the cytoplasmic tail, and this is called outside-in signaling (Kim et al., 2011; Tadokoro et al., 2003).
Cell attachment is regulated by the formation of cell adhesion complexes, of which integrin is an essential component. This process also operates as the motor behind cell motility. As the cell moves, it adheres to a substrate in front and releases the one at the rear. After release, integrin molecules are recycled back into the cytoplasm, carried across the cell and added back to the membrane on the other side for a fresh attachment (Jacquemet et al., 2013).
Integrin subunits can selectively bind to different ligands, such as fibronectin, vitronectin, collagen and laminin. This means integrin expression patterns define which extracellular substrates the cell can bind to. Both α and β subunits of integrin can recognize and bind to the Arg-Gly-Asp (RGD) motif, but the specific ligands for each integrin are further defined by the amino acid sequence surrounding this RGD sequence (Jacquemet et al., 2013).
These complexes can regulate the activity of several kinases, phosphatases and adaptor proteins, including Src kinases, focal adhesion kinases (FAKs), SH2 domain-containing protein tyrosine phosphatase 2 (SHP2) and receptor type tyrosine protein phosphatse α (RPTPα). In turn, these components can regulate different substrates to promote adhesion to an exterior surface or another cell. Depending on integrin regulation, the cell can experience different outcomes, ranging from cell division and growth to programmed cell death (Jacquemet et al., 2013).
As integrins lie at the interface of the cell and microenvironment, their role in tumor progression is not unexpected. Studies have demonstrated their connection with several types of cancer, particularly during metastases and angiogenesis (Marelli et al., 2013).
For example, β1 integrins, which are involved in regulating cell proliferation and adhesion, have been implicated in increasing therapeutic resistance in solid cancers and hematopoietic malignancies (Sayeed et al., 2013; Berghoff et al., 2013). Many integrins have been implicated in cancerous growth, including αVβ3, α1β1 and others (Bolley et al., 2013; Berghoff et al., 2013).
However, as they represent cell surface receptors, they are also in an ideal position to become pharmacological targets. There has been some promising work in this area looking at β3 and β5 (Lautenschlaeger et al., 2013), and researchers expect other integrins to follow.