Peter N. Devreotes, Ph.D.
Johns Hopkins University School of Medicine
725 N. Wolfe St., 114 WBSB
Baltimore, MD 21205
Research TopicGenetic analysis of chemotaxis in eukaryotic cells
Research Topic: Genetic analysis of chemotaxis in eukaryotic cells
Many cells have an internal “compass” that allows them to detect and move along extracellular chemical gradients in a process referred to as chemotaxis or directed cell migration. In embryogenesis, chemotaxis is used repeatedly to rearrange cells, for instance, during primordial germ cell migration, organ formation, and wiring of the nervous system. In the adult, chemotaxis mediates normal trafficking of immune cells and is critical for inflammation. It also participates in wound healing, in maintenance of tissue architecture, and allows stem cells to target to and persist in their niches.
Chemotaxis bias depends on a network composed of multiple signaling pathways. Several years ago, we discovered that chemoattractants activate PI3Ks producing an accumulation of PIP3 at the leading edge of amoebae. We now know that this mechanism is conserved in neutrophils and many other types of eukaryotic cells. Unregulated production of PIP3, as occurs in cells lacking the tumor suppressor PTEN, causes many ectopic projections and impairs the directional response of migrating cells. Thus, localized PIP3 production is an important conserved mechanism mediating chemotactic bias. However, additional pathways act in parallel or redundantly with PIP3.
In our search for parallel pathways, we have found that TorC2 is activated at the leading edge of the cell and causes the localized activation of PKBs and phosphorylation of PKB substrates. The absence of these phosphorylation events in cells lacking PiaA leads to a defect in chemotaxis. This pathway acts in parallel with PIP3 to mediate the chemotactic response. It has recently been found that the TorC2 mechanism is conserved in chemotaxing neutrophils. Most recently, using TIRF, we have found that signaling events propagate in waves along the basal surface of the cell. We are investigating how these spontaneous signaling waves coordinate the activity of the cytoskeleton to make cellular protrusions.
Our long term goal is acomplete description of the network controlling chemotactic behavior. We are analyzing combinations of deficiencies to understand interactions among network components and carrying out additional genetic screens to identify new pathways involved in chemotaxis. A comprehensive understanding of this fascinating process should lead to control of pathological conditions such as inflammation and cancer metastasis.