DOCK180 and PIP3 Gradient Orchestrate Cell Movement That May Offer Clues to Blocking Metastasis

AbstractFrom 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. Dr. Vuori is also a member of the Editorial Board of Cancer Biology and Therapy.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."Vuori's colleagues in the study included Jean-Francois Cote, now of the Clinical Research Institute of Montreal, and Andrea B. Motoyama and Jason Bush, both of the Burnham Institute.This work was supported by grants from the National Institutes of Health and a fellowship from the Terry Fox Foundation awarded by the National Cancer Institute of Canada.The Burnham Institute, founded in 1976, is an independent not-for-profit biomedical research institution dedicated to advancing the frontiers of scientific knowledge and providing the foundation for tomorrow's medical therapies. The Institute is home to three major centers: the Cancer Center, the Del E. Webb Neuroscience and Aging Center established, and the Infectious and Inflammatory Disease Center. Since 1981, the Institute's Cancer Center has been a member of the National Cancer Institute's prestigious Cancer Center's program. Discoveries by Burnham scientists have contributed to the development of new drugs for Alzheimer's disease, heart disease and several forms of cancer. Today the Burnham Institute employs over 700, including more than 550 scientists. The majority of the Institute's funding derives from federal sources, but private philanthropic support is essential to continuing bold and innovative research. For additional information about the Institute and ways to support the research efforts of the Institute, visit www.burnham.org.

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