Article about a coordinator protein which synchronizes other proteins that drive cell invasion, and its implication for cancer proliferation and prediction. Written for MBI, FoS and NUS.

Based on: The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration; Read here too: mbi.nus.edu.sg/science-features/bridging-the-bpgap-in-metastasis/ + phys.org/news/2023-04-cancer-cells-migrate-paves-therapies.html

Like deactivating a bomb by cutting the correct wire, what if we can disable a cancer cell from spreading by “terminating” the right switch in its machinery? A team of researchers from the Mechanobiology Institute and the Department of Biological Sciences, National University of Singapore, with their local and overseas collaborators, may have identified that key component — a scaffold protein known as BPGAP1 — and how it operates. Their research has been featured in Molecular Biology of the Cell, published by the American Society for Cell Biology, in its “Forces On and Within Cells” Special Issue.

Led by Dr. Darren Wong with the guidance of Assoc. Prof. Low Boon Chuan, the team discovered how BPGAP1 synchronizes two key proteins responsible for cell migration, namely, Rac1 and RhoA, which Dr. Wong described as “the two hands working hand-in-hand to move the cell”. This migrative ability of the cell is what enables metastasis, which is when cancer cells depart from their original site, travel through our bloodstreams and invade distant organs; It is also what makes cancer so devastatingly deadly.

Being a complicated and multistep process, effective treatment options for metastasis are limited and cater more towards symptom relief at advanced stages than eliminating root causes. Unravelling the underlying mechanistic action of BPGAP1 may be the key to apprehending the rouge traversal of cancer cells and paving the way to create more directed approaches to cancer intervention.

The mobility of a cell is propelled by changes in its cytoskeletal organization, which in turn is governed by a set of proteins, including a group known as GTPases. GTPases can be described as molecular switches which activate (or inactivate) specific pathways that carry out cellular functions. In this case, GTPases Rac1 and RhoA work with each other to remodel the cytoskeleton by mediating different pathways — Rac1 enables the cell to grip onto its surroundings and pull itself forward by forming sheet-like protrusions in the membrane (known as lamellipodia), while RhoA enables the cell to adhere to surfaces and push the cell forward using contractile forces. Though functionally similar, these two processes typically antagonize each other and do not take place in the same place and at the same time, but are both needed to ensure effective cell movements. Hence, there is a need to orchestrate the proteins in a way that their functions are in sync.

While most scientists have already recognize Rac1 and RhoA’s involvement in cell movement, Dr. Wong and his team found that another protein, BPGAP1, not only has interactions with both of them, but is also highly expressed in cancer cells and extensively promotes cell migration. This led them to theorize that BPGAP1 acts as a scaffold and coordinator between the two GTPases, therefore serving as a key regulator of their activities. To validate this, they used various models, assays and biomaterials, and manipulated metastatic breast cancer cells to uncover and piece together the working mechanism of BPGAP1.

Figure 1: Schematic showing the interactions between BPGAP1 and GTPases Rac1 (Top Half) and RhoA (Bottom Half)

They found that BPGAP1 binds to an inactive Rac1, and together, they relocate to the lamellipodia. To activate Rac1, BPGAP1 has to recruit another protein known as Vav1 while the cell is physiologically stimulated by epidermal growth factors. When all these factors are in place, the team spotted enhanced cell migration behaviours, such as the cell flattening out and spreading, growing longer protrusions, having a boost in mobility and a better ability to extrude itself from blood vessels.

But how does RhoA fit into all these? As opposed to Rac1, BPGAP1 inactivates RhoA by binding one of its domains to the latter. Thus, BPGAP1 coordinates the activities between the two GTPases by dually “switching off” RhoA while “switching on” Rac1. These repeated cycles of on/off switching ultimately reinforce the cell’s mobility.