From birth until death, our cells migrate: nerve cells make their vital connections, embryonic cells move to the proper places to form organs, immune cells zero in to destroy pathogenic organisms, and cancer cells metastasize, spreading deadly disease through the body. Scientists studying these migrations didn't know how cells determined where to go. Until now.
A Burnham Institute study has identified a fragment of a protein that senses chemicals that induce a cell to move into the right direction. Guided by this fragment, the molecular machinery needed for cell movement begins accumulating at the leading edge, or front of a cell in response to a variety of chemical messengers, and begins the directed process of migration. The study, led by associate professor and Burnham Cancer Center Acting Director Kristiina Vuori, M.D., Ph.D., appears in the August issue of Nature Cell Biology.
The finding is the first to determine the molecule responsible for internally choreographing directed cell migration. The experiments were conducted in several widely used laboratory models, but the molecule exists in nearly all animals, from roundworms to mammals, and likely has a conserved function throughout species. Knowing exactly what triggers cellular migration can help develop treatments that halt cancer metastasis and immune disorders like arthritis and asthma.
"Previous studies by us and others have identified how a migrating cell 'gets its wheels' and, mechanistically, is able to move. In this study, we have now determined how these wheels become pointed in the right direction", said Vuori. "We now know this is done using a protein that holds true in most cellular systems. Seeing how this process directs cells can help us better address a host of diseases that result from too little or too much cell movement, or from cells moving in the wrong direction and to the wrong place."
Dr. Vuori and her team found a molecule called DOCK180, a key signaling protein that binds to PIP3. PIP3 is a lipid that accumulates on the leading edge of a cell about to move, usually in response to a number of outside cellular attractants like chemokines, growth factors and other molecules. Meanwhile at the hind end of the cell, enzymes degrade the PIP3 lipid, creating a gradient from one end of the cell to the other.
It is this PIP3 lipid gradient that sets the cell into motion toward the right direction. The PIP3-binding portion of DOCK180 senses the gradient, and DOCK180 starts accumulating at the leading edge of the cell. Along with it, DOCK180 brings a host of additional molecules to the leading edge, triggering a series of internal events that begin moving the cell forward. "We see a protrusion form first, in which the cell changes shape and extends towards the direction it is about to go, followed by movement of the rest of the cell," Vuori said.
Now, the researchers are looking at developing a three-dimensional picture of PIP3 -binding domain's molecular structure. "We are currently planning these structure studies with our collaborators here at the Burnham," Vuori said. "If we know its molecular structure, we hope to be able to make small chemicals that inhibit inappropriate cell migration, including the types seen in metastatic cancer cells."