Paxillin is an intracellular protein. This protein, weighing approximately 68 kilodaltons, resides in the cytoplasm and is present in nearly all tissues throughout the body. Discovered in 1990, paxillin plays a part in numerous cellular activities. Its fundamental nature involves interacting with many other proteins, coordinating various internal processes.
Paxillin’s Role in Cell Adhesion and Migration
Cells maintain their position and move within tissues by forming specialized structures called focal adhesions. These structures serve as molecular anchors, connecting the cell’s internal framework to its external environment, the extracellular matrix. Paxillin is a component of these focal adhesions, acting as an early recruit to forming attachment sites. It helps bridge the gap between the cell’s inner “skeleton,” the actin cytoskeleton, and extracellular matrix proteins through transmembrane proteins called integrins.
This physical connection is fundamental for cells to adhere firmly to their surroundings. Beyond simple attachment, paxillin’s presence at focal adhesions also enables cells to move. By linking the internal actin network to the outside, paxillin facilitates the dynamic assembly and disassembly of these anchors, a required process for cell movement across surfaces. This continuous restructuring of adhesion sites allows cells to move from one location to another, a process seen in contexts like wound healing and immune responses.
Paxillin as a Molecular Signaling Hub
Beyond its structural role in cell adhesion, paxillin functions as a molecular signaling hub. It does not carry out enzymatic reactions on its own, but instead provides specific docking sites for a variety of other proteins. These sites are found in distinct regions of paxillin, such as its LD motifs and LIM domains, allowing it to bind numerous signaling and structural molecules. This assembly brings different active proteins into close proximity at specific cellular locations, such such as focal adhesions, enabling effective communication.
A significant mechanism controlling paxillin’s interactions is phosphorylation, a process where a phosphate group is added to the protein. This modification acts like an “on/off switch,” altering paxillin’s shape and affinity for other molecules. For instance, phosphorylation at specific tyrosine residues, like Tyr31 and Tyr118, by kinases such as FAK and Src, creates new binding sites for adapter proteins. This dynamic regulation allows paxillin to receive signals from the cell’s exterior, integrate them, and then transmit them inward to influence diverse cell behaviors, including cell growth and movement.
The Connection Between Paxillin and Cancer Metastasis
The regulated functions of cell adhesion, migration, and signaling, normally controlled by proteins like paxillin, become dysregulated in cancer, particularly during metastasis. Metastasis refers to the spread of cancer cells from their original tumor site to distant parts of the body, a process responsible for the vast majority of cancer-related deaths. In many aggressive cancers, paxillin’s expression levels are altered; it can be overproduced or exist in a constantly “switched on” state through persistent phosphorylation.
This dysregulation of paxillin can lead to the breakdown of stable cell adhesions, which normally keep cells in place. When adhesions become unstable, cancer cells can detach from the primary tumor and invade surrounding tissues. Increased phosphorylation of paxillin, particularly at tyrosine residues 31 and 118, is often observed in metastatic cancers and promotes enhanced cell motility. This heightened migratory capacity allows cancer cells to move uncontrollably, facilitating their invasion into blood or lymphatic vessels and subsequent dissemination. Paxillin also contributes to cancer cell invasion by influencing processes like epithelial-mesenchymal transition (EMT), where cells acquire migratory properties, and by promoting the formation of invadopodia, specialized structures that help cancer cells degrade surrounding tissue.
How Paxillin Senses Physical Forces
Cells constantly interact with and sense the physical properties of their environment, such as tissue stiffness. This ability is known as mechanotransduction, where physical forces are converted into biochemical signals inside the cell. Paxillin acts as a molecular mediator in this process. It helps translate external physical cues into internal cellular responses.
For example, the stiffness of the extracellular matrix can influence paxillin’s behavior and subsequent cell functions. Paxillin’s phosphorylation can affect how other proteins, such as vinculin, are recruited to focal adhesions, influencing how cells sense and respond to mechanical tension. Paxillin’s involvement in the tension within adhesions further underscores its role in translating physical forces into signals that guide cell decisions, including whether to grow, move, or differentiate.