Affiliation: UCSD SOM
Assistant Professor of Medicine
Seth Field received his B.S. degree in Biology at the Massachusetts Institute of Technology and M.D. and Ph.D. degrees at Harvard Medical School. He was a postdoctoral fellow at Harvard in the Department of Systems Biology. He was awarded a Howard Hughes Medical Institute physician-postdoctoral fellowship in 1999 and a Burroughs Wellcome Fund Career Award in 2004.
Our lab studies the phosphoinositides, a group of signaling molecules involved in growth factor signaling, membrane trafficking, and probably many more functions. Mutation of one of the phosphoinositide signaling pathways recently has been discovered to be the single most common mutation found in human cancers. Impaired phosphoinositide signaling, in part, underlies the defect in type 2 diabetes mellitus. Small molecules that modulate phosphoinositide signaling are currently under development as drugs for heart disease, autoimmune diseases, and cancer. However, many aspects of phosphoinositide function remain poorly understood.
We are taking several approaches to identify novel functions for this interesting group of signaling molecules. One approach uses fluorescence microscopy of living mammalian cells expressing green fluorescent protein reporters for each of the phosphoinositides. Another approach involves a screen of the Drosophila proteome to identify novel phosphoinositide-binding proteins. Both approaches have yielded new and unexpected functions for the phosphoinositides. For example, we have identified an interesting role for PtdIns(4,5)P2 at the cleavage furrow during mitotic cytokinesis. We have many projects to study our new phosphoinositide binding proteins (including their role in cytokinesis) and to develop new approaches to study phosphoinositide function. Because of the broad role for phosphoinositides in the cell, we are always ready to delve into new areas of cell biology as our research leads us.
Two general strategies to identify novel functions for phosphoinositides
* Live cell imaging of phosphoinositides
Changes in the level or sub-cellular localization of a phosphoinositide can provide a clue to new functions.
Proof of principle: A role for PtdIns(4,5)P2 at the cleavage furrow during cytokinesis
We have found that PtdIns(4,5)P2 specifically accumulates at the cleavage furrow during cytokinesis. We have also shown that two of the PI(4)P-5-kinases that generate PtdIns(4,5)P2 also localize to the cleavage furrow. Furthermore, interference with PtdIns(4,5)P2 interferes with cytokinesis. Finally, we have evidence that PtdIns(4,5)P2 may be the key to answering an important unsolved issue in cytokinesis: what causes the plasma membrane to adhere to the contractile ring so that it invaginates during cytokinesis?
Investigation of this role for PtdIns(4,5)P2 at the cleavage furrow is the basis of several projects in the Field laboratory. As a good start, we have identified a novel PtdIns(4,5)P2 binding protein (see below) that functions during cytokinesis.
PtdIns(4,5)P2 accumulates at the cleavage furrow during cytokinesis.
* Proteome-wide screen for new phosphoinositide-binding proteins
We have devised a high-throughput screen to identify new phosphoinositide-binding proteins. After screening approximately 1/3 of the Drosophila proteome we have already identified many new phosphoinositide-binding proteins. Each of these provides the basis for new projects to study questions of structure-function, and to study the function of each protein as a mediator of the effects of phosphoinositides within the cell.
For more information about my lab, visit the lab website at http://sethfield.ucsd.edu/
References From PubMed (NCBI)