Scaffold proteins act as molecular organizers within our cells, bringing together components of a signaling pathway to facilitate their interaction. One such organizer is Tks5, short for Tyrosine kinase substrate with 5 SH3 domains. First identified as a substrate for the Src tyrosine kinase, Tks5 is a large protein involved in processes that change cell shape and movement. Its discovery has opened new avenues for understanding how cells physically interact with their environment.
Defining the Tks5 Protein
Tks5’s function is encoded in its structure, which contains distinct parts, or domains. The protein has two main functional domain types. At one end is a Phox homology (PX) domain that binds to specific lipids on the inner surface of the cell membrane. This interaction anchors Tks5 to the membrane, ensuring it is positioned correctly.
The rest of the protein contains five Src homology 3 (SH3) domains. These SH3 domains function as docking sites, each recognizing and binding to specific sequences on other proteins. This allows Tks5 to recruit different signaling proteins to one location. The coordinated action of its PX and SH3 domains allows Tks5 to assemble the molecular machinery for complex cellular tasks.
Cells produce different forms of Tks5. The full-length version, Tks5α, contains the PX domain followed by the five SH3 domains. Shorter forms that lack the PX domain also exist but cannot contribute to forming invasive structures. In cancer cells, the long, PX-domain-containing form is predominantly expressed and active.
Function in Invadopodia Formation
A primary role of Tks5 is its function in forming invadopodia. These are actin-rich protrusions that cancer cells extend from their surface to degrade the surrounding tissue. By breaking through the extracellular matrix that holds tissues together, invadopodia enable cell invasion. The formation of these structures is an organized process that depends on the assembly of numerous proteins, a task suited for Tks5.
The process begins when Tks5 is anchored to the plasma membrane by its PX domain. Once in position, Tks5 is phosphorylated by the Src kinase, which enhances its scaffolding function. This activation allows its five SH3 domains to recruit other proteins needed to build the invadopodia.
Proteins recruited by Tks5 include cortactin, which helps assemble actin filaments, and the adaptor protein Grb2. Tks5 also brings in matrix metalloproteinases (MMPs), enzymes that degrade the extracellular matrix. Tks5 serves as the platform upon which this invasive machinery is constructed. Without Tks5, these components fail to assemble correctly, and functional invadopodia cannot form.
The Link Between Tks5 and Cancer Metastasis
Metastasis, the spread of cancer from a primary tumor to distant organs, is the main reason for cancer-related mortality. This process requires cancer cells to become mobile and invasive, and invadopodia are part of this process. By degrading the extracellular matrix, invadopodia allow cancer cells to break out of the original tumor, enter blood or lymphatic vessels, and establish new tumors.
A strong connection exists between Tks5 and aggressive cancers. Elevated levels of Tks5 are observed in invasive human cancers like melanoma, glioblastoma, and breast cancer. Cancer cells engineered to have high levels of Tks5 are more invasive and have a greater capacity to form metastases in laboratory models.
Conversely, when Tks5 expression is blocked in aggressive cancer cells, their ability to form invadopodia is impaired. These cells become less invasive and show a reduced potential for metastasis. This evidence highlights Tks5’s role in cancer progression, making it a molecule of interest in oncology. The level of Tks5 in a tumor could potentially serve as a prognostic marker for metastasis.
Targeting Tks5 in Cancer Treatment
Given its role in metastasis, Tks5 is a target for new cancer therapies. The goal is to disrupt its function, preventing invadopodia formation and halting the spread of cancer cells. Developing drugs to block Tks5 presents a unique set of challenges.
The difficulty lies in Tks5’s nature as a scaffold protein. Unlike enzymes with active sites that can be blocked by small-molecule inhibitors, its function relies on protein-protein interactions across large surface areas. These interactions are difficult to disrupt with traditional drug discovery methods.
Researchers are exploring several strategies to inhibit Tks5. One approach is to prevent Tks5 from anchoring to the cell membrane by developing molecules that block its PX domain. Another avenue involves creating protein-protein interaction inhibitors designed to obstruct the SH3 domains of Tks5, preventing them from docking with their binding partners. While still experimental, these approaches hold promise for developing a new class of anti-metastatic drugs.