Research Dr. Darren Wong led and Assoc. Professor Low Boon Chuan revealed how BPGAP1 synchronizes two critical proteins involved in cell migration, the GTPases Rac1 and RhoA.
; this is what makes cancer deadly.
Because metastasis is a complex and multistep process, effective therapy options for advanced stages are limited and focus more on symptom management than on addressing the root cause.
Unfolding the BPGAP1 molecule
Unraveling the underlying molecular activity of BPGAP1 may hold the key to understanding cancer cell transition and pave the way for more targeted cancer therapy.
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Cell motility is accelerated by changes in its cytoskeletal architecture, mediated by a group of proteins known as GTPases. A GTPase is a molecular switch that activates (or deactivates) specific pathways to carry out cellular activities.
Rac1 and RhoA GTPases cooperate to remodel the cytoskeleton by mediating different pathways—Rac1 enables the cell to sense, grasp its surroundings, and crawl by forming sheet-like membrane protrusions (known as lamellipodia), while RhoA creates adhesion sites and contractile force. push the cell forward.
These two processes are often contradictory and do not occur at the same time or place, but are required for successful cell migration. As a result, proteins must be orchestrated in such a way that their actions are synchronized.
They found that BPGAP1 binds to inactive Rac1 and the two move to lamellipodia. BPGAP1 must recruit another protein known as Vav1 to activate Rac1 when the cell is physically stimulated by epidermal growth factors.
Cell Migration Behavior Observed
When all of these elements were present, the team observed improved cell migration behaviors, such as cell flattening and spreading longer protrusions that grew, increased motility, and a better ability to remove itself from blood vessels.
Although scientists are aware of the role of Rac1 and RhoA in cell migration, Dr. Wong and his colleagues discovered that another protein, BPGAP1, not only interacts with both of them, but is also highly expressed in cancer cells and widely promotes cell migration.
They then discovered that BPGAP1 serves as a scaffold and coordinator between the two GTPases, acting as a critical regulator of their activity.
They worked with clinical scientists both locally and internationally to confirm this. They discovered and integrated the working mechanism of BPGAP1 using different models, assays and biomaterials, especially in metastatic breast cancer cells.
So where does RhoA come into all this? Unlike Rac1, BPGAP1 inhibits RhoA by binding to one of its domains. Thus, by turning RhoA “off” and Rac1 “on,” BPGAP1 controls the actions of the two GTPases. Cell motility is ultimately enhanced by these repetitive on/off cycles.
Timing is also important as it acts as a pacemaker to coordinate Rac1 activation with RhoA inactivation. Such close dynamics allow the cell to respond quickly to any shock. Not surprisingly, the researchers found that if BPGAP1 loses its function and cannot regulate the two GTPases, the ability of the cell to migrate is impaired.
By identifying the role of BPGAP1 in controlling cell movement and its higher involvement in metastatic cells, it is clear that BPGAP1 is central to cell migration and metastasis.
In addition, its increase in all stages of breast cancer, as well as in malignancies of lung, pancreas, cervix, colon, ovary and stomach, suggests that it plays a role in all types and stages of cancer.
Consequently, the identification of BPGAP1 has great potential for cancer prediction and treatment. “We can use BPGAP1 both as a marker for cancer prognosis and as a target for cancer intervention among different types of cancer,” said Dr. Wong explained. “We hope that with this advance, we can inspire new approaches for therapeutic designs in cancer and metastasis.”
Reference
- The scaffolding RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration – (https:www.molbiolcell.org/doi/10.1091/mbc.E21-03-0099)
Source: Medium
