A pod of hippos next to a group of cells. The physical contacts between the cells and their surroundings are highlighted and illustrated as close-ups of cell-cell junctions and focal adhesions. Forces experienced by the cells are shown in white arrows. Illustration by Dr. Leonora Martinez-Nunez.
Happy Hippo Day!!!
For many people, “hippo” brings to mind an equal parts cute and terrifying semi-aquatic mammal from the continent of Africa. For many biologists, “hippo” also brings to mind a cellular signaling pathway that is critical to life as we know it. In fact, the biological Hippo signaling pathway is named after the animal!
Hippo signaling controls organ size and cell identity.
Aptly named after the third largest land mammal on earth, the Hippo pathway helps control the size of our organs by telling our cells when to, and when not to multiply. But just like the Hippopotamus can do way more than just eating almost 90lbs of grass per night (for example, they can also open their jaw to almost a full 180o), Hippo signaling can do a lot more than controlling the size of our organs. Hippo signaling can also help cells sense the forces around them and decide whether or not to divide and make more cells. One of the ways Hippo signaling does this is through reacting to forces that push and pull on a cell.
An absolutely terrifying image of a hippo running around with its mouth open almost 180o. Fun fact, hippos can run on land up to 19mph over short distances, and they are actually not very strong swimmers. To traverse deep water, they sink to the bottom and bounce back up to the surface repeatedly until they have made it back into shallower waters.
To help us understand this process of tension sensing, let’s use our imagination. Let’s envision ourselves in a thick crowd of people at a concert. We’re standing there enjoying the music and gingerly trying not to touch all the sweaty strangers around us. Then, someone bumps into us and knocks us over. Unless you have done a lot more meditation than I have, you can probably imagine your emotions changing rapidly from happy to angry. This change in emotions might even elicit a change in our actions, like confronting the person who bumped us or leaving the concert. Just like our mood and behavior can change when we’re subjected to the physical forces of being in a crowd, the identity and behavior of cells in our bodies can also change when they are pushed and pulled by their environment.
Hippo at UMass Chan BMB.
Even though there is plenty of water here in central Massachusetts for a pod of hippos to terrorize, the only hippopotamuses to be seen are at the Franklin Zoo in Boston. However, there is plenty of “Hippo” here at UMass Chan! Our department is home to one Hippo enthusiast Dr. Dan McCollum. Dr. McCollum’s lab studies how the Hippo pathway is able to sense these pushing and pulling forces. Specifically, his lab focuses on how Hippo signaling components receive information about mechanical forces at cell-cell junctions, which is a term used to describe where and how cells are in physical contact with each other.
Just like the density of people in a concert crowd, cells in our body need to be at just the right density, not too crowded or too sparse. The Hippo pathway is required for maintaining the right number of cells in a tissue, which is critical for maintaining the integrity of the tissue, healing wounds, and preventing cells from continuing to multiply even when they are crowded (which is what happens in cancer).
While looking at cell-cell junctions, Dr. McCollum’s lab identified a protein called TRIP6 that helps translate physical forces experienced by the cell into Hippo pathway activity. Because the physical forces experienced by cells depends on how crowded they are, TRIP6 allows the Hippo signaling pathway to tell normal cells to multiply when they are not crowded by other cells, and to stop multiplying when they become crowded. These controls are typically lost in cancer cells, which keep multiplying even when they are crowded. Without TRIP6 to regulate the Hippo pathway, cells can no longer make decisions about whether or not to multiply based on how crowded they are.
A figure from Dutta et al, 2018; a paper from Dr. McCollum's lab published in EMBO Reports. All three images are different color combinations of the same image, which is a close up on a group of cells grown in a dish. In the far right image, blue represents cell nuclei (labeled with DAPI), green represents hippo signaling component LATS1 and red represents tension sensation modulator TRIP6. Single-color images showing only LATS1 or only TRIP6 staining in greyscale shows how these components critical for sensing physical force in a cell are located at the borders of cells where they are in contact with their neighbors.
Hippo might save the day.
Scientists around the world are studying how cells sense and respond to physical forces not only because they love hippos, but because misregulation of Hippo signaling can cause cancer. If cells don’t know when to stop multiplying, they can easily start growing like crazy to form tumors. Dr. McCollum’s lab is part of a global effort to figure out how Hippo signaling is normally regulated in our cells so we can develop new methods to treat various cancers.
I’ll leave you with one last fun biochemistry fact about hippos the animal: hippopotamus skin secretes a liquid that has antibacterial activity AND can act as a sunscreen! The compounds in the oil absorb UV light, thus protecting the skin of the hippo from the intense rays of the sun. To learn more about the biochemistry of what has been called hippo “blood sweat,” check out this Nature article.
