Bridging the (BP)GAP in metastasis

National University of Singapore (NUS) researchers have discovered how a scaffolding protein synchronizes, in space and time, two important regulatory proteins driving cell migration and revealed its potential as a target to halt metastasis.

Cancer is one of the leading causes of death worldwide with nearly one in six deaths.  Metastatic cancers are responsible for the majority of cancer-related deaths but it remains poorly understood. It occurs when cancer cells break off from the original tumour and spread to other parts of the body.

A research team led by Associate Professor LOW Boon Chuan from the Department of Biological Sciences, the NUS College and the Mechanobiology Institute, NUS, with their local and overseas collaborators, have identified a scaffold protein known as BPGAP1 that could potentially cause cancer cells to move through blood vessels. They have also discovered how it works. Their research has been featured in the journal Molecular Biology of the Cell.

The research team discovered how BPGAP1 synchronizes two key proteins responsible for cell migration — namely, GTPases Rac1 and RhoA, which is described as “the two hands which work hand-in-hand to move the cell”. The migrative ability of the cell is what enables metastasis, a process in which cancer cells depart from their original site, travel through the bloodstreams, and invade distant organs.

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

The mobility of a cell is propelled by changes in its cytoskeletal organisation, which in turn is governed by a set of proteins, including a group known as GTPases. GTPase can be described as a molecular switch which activates (or inactivates) specific pathways to 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 sense, grip onto its surroundings and crawl by forming sheet-like membrane protrusions (known as lamellipodia), while RhoA generates adhesion sites and contractile force to power the cell forward. These two processes typically antagonize each other and do not take place at the same place and time, but are needed to ensure effective cell movements. It is important that these proteins are orchestrated in a way such that their functions are in sync with each other.

While scientists recognise Rac1 and RhoA’s involvement in cell movement, the researchers found that another protein, BPGAP1, does not only have interactions with both of them, but is also highly expressed in cancer cells and extensively promotes cell migration. They later found that BPGAP1 acts as a scaffold and coordinator between the two GTPases, therefore serving as a key regulator of their activities.

By understanding BPGAP1’s role in controlling cell movement, coupled with its greater presence in metastatic cells, it is evident that BPGAP1 is involved in cell migration and metastasis. Moreover, with it being upregulated across all stages of breast cancer, and also in cancers of the lungs, pancreas, cervix, colon, ovary and stomach, this implies a potential role that BPGAP1 plays in the formation of different types and stages of cancer.

BPGAP1 can potentially be used both as a marker for cancer prognosis and a target for cancer intervention across different cancer types. With this discovery, it presents new channels for cancer prediction and mediation.

Figure 1: Schematic showing the interactions between BPGAP1 and GTPases Rac1 (Top Half) and RhoA (Bottom Half). BPGAP1 coordinates the activities between the two GTPases by “switching off” RhoA while “switching on” Rac1 and vice versa. These repeated cycles of on/off switching increase the mobility of the cell.

Reference

Wong DCP; Pan CQ*; Er SY; Thivakar T; Tan ZYR, Seah SH; Chua PJ; Jiang T; Chew TW; Chaudhuri PK; Mukherjee S; Salim A; Thike AA; Koh CG; Lim CT; Tan PH; Bay BH; Ridley AJ; Low BC*, “The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration” MOLECULAR BIOLOGY OF THE CELL DOI: 10.1091/mbc.E21-03-0099 Published: 2023.

[Original article from MBI Science Features.]