Cells exist in a constant, dynamic conversation with their physical surroundings, a process fundamental to how tissues are built and maintained. A primary way a cell “feels” its environment is through integrin signaling. This system allows a cell to understand its location, what to hold onto, and whether it should grow or move. As a sensory mechanism, it translates physical cues from outside the cell into biochemical messages inside, guiding a cell’s decisions and contributing to the function of its tissue.
The Building Blocks of Integrin Communication
Integrins are specialized receptor proteins that physically span the cell’s outer membrane. Each integrin is composed of two distinct protein chains, an alpha (α) and a beta (β) subunit. Different combinations of these subunits form various integrins, each able to recognize specific external molecules.
These proteins interact with the extracellular matrix (ECM), a complex meshwork of proteins and carbohydrates that surrounds cells. The ECM provides structural support to tissues and is a dynamic environment rich with information. Key ECM proteins include collagen, which gives tissues their strength, and fibronectin, a glycoprotein that connects collagen fibers to the integrins on the cell surface.
Transmitting the Signal Across the Membrane
Integrin signaling is a bidirectional process, meaning information flows from the outside-in and from the inside-out. This two-way communication allows cells to both sense and actively respond to their surroundings.
“Outside-in” signaling begins when an integrin’s external domain binds to a ligand in the ECM, such as fibronectin. This binding triggers a conformational change in the integrin, causing its intracellular portions to move apart and unmask binding sites on its cytoplasmic tails. These newly exposed sites recruit various intracellular signaling proteins like Focal Adhesion Kinase (FAK).
The clustering of integrins and the accumulation of these proteins lead to the formation of large complexes known as focal adhesions. These structures convert the physical signal into a cascade of chemical reactions inside the cell. Conversely, “inside-out” signaling allows the cell to control its own adhesiveness. This process starts with internal signals that activate a protein called talin, which then binds to the integrin’s beta subunit. This interaction triggers a conformational change that extends the integrin into an upright, high-affinity state, ready to bind to the ECM.
How Integrin Signalling Directs Cell Behavior
The biochemical cascades initiated at focal adhesions direct a range of cellular behaviors, ensuring a cell’s actions are appropriate for its location. One primary outcome is cell adhesion, the process by which cells anchor themselves to the ECM. This attachment provides physical security and generates pro-survival signals that suppress anoikis, a form of programmed cell death triggered when cells become detached.
Integrin signaling is also necessary for cell migration, which involves a regulated cycle of forming and breaking connections with the ECM. At the front of a moving cell, inside-out signals activate integrins to form new attachments, while signals at the trailing edge cause the disassembly of old adhesions. This coordinated activity is required for processes like wound healing.
Integrin signals also collaborate with other pathways to regulate cell proliferation. Many cells will only divide if they are anchored to the ECM, and these signals can work with messages from growth factors to prompt a cell to enter the cell cycle.
Integrin Signalling in Disease Progression
Disrupted integrin signaling contributes to the progression of numerous diseases, often through changes in integrin expression or their associated pathways. In cancer, faulty signaling can drive metastasis. Cancer cells may alter their integrin expression, allowing them to detach from a primary tumor, navigate the ECM, and invade blood vessels. Aberrant signals also promote the survival of these detached cells, helping them form secondary tumors.
Fibrosis, or the scarring of organs, is another example. Chronic injury can lead to persistent activation of integrins on fibroblasts, causing them to overproduce ECM components like collagen. This buildup of dense, scar-like tissue impairs organ function.
This system is also implicated in autoimmune diseases. The migration of immune cells into tissues is controlled by integrins, and dysregulation can incorrectly direct these cells to healthy tissues. This can cause chronic inflammation in conditions like rheumatoid arthritis or inflammatory bowel disease.