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Seth Corey, MD, MPHProfessor of Pediatrics
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Our laboratory studies oncogene signaling. Src family protein kinases and PI 3’kinase regulate a variety of critical cellular functions, such as proliferation and cytoskeletal reorganization. To do this, our laboratory employs a wide range of molecular and cellular approaches, including molecular biology, confocal microscopy, RNAi, and systems biology. Diseases studied include myeloid leukemias, breast cancer, bone tumors, and diabetes.
1. More specifically, we are establishing the contributions made by the Src kinase Lyn in blood cell production (hematopoiesis). By examining how the G-CSF (granulocyte colony stimulating factor) Receptor drives the production of neutrophils, we found that the Src kinase Lyn is indispensable. One of Lyn’s downstream effectors is PI 3’kinase, which in turn activates the serine kinase Akt. We found that Lyn and PI 3’kinase are excessively active in several types of leukemia. Leukemia results from two major catatstrophic events: unregulated growth and survival and a block in differentiation. We are currently investigating how aberrant Lyn and PI 3’kinaser activities perturb each behavior.
Children who have congenital neutropenia and are treated with G-CSF frequently develop acute leukemia in association with a mutated G-CSF Receptor. This receptor is differentiation-defective. We are looking at the mechanisms by which this receptor drives leukemogenesis. This serves as a model for a more common form of adult leukemia.
2. We discovered a new cytoskeletal protein in a yeast two hybrid screening with Src kinase Lyn as bait. This protein is called Cdc42-interacting protein #4, and it is a member of a new family of proteins (F-BAR proteins). We have made a knock-out of this mouse and have employed siRNA to validate our findings that CIP4 contributes to membrane remodeling, receptor endocytosis, and cellular motility.
3. Through discovering functional interactions like Lyn and PI 3’kinase and new components such as CIP4, we realized several years ago that we needed to use new approaches to further unravel the mysteries of cell signaling. With the goal of simplifying the complexity of biological systems, we began a collaboration with computer scientist, chemical engineers, and mathematicians to model hematopoiesis. We are also applying this approach to design multi-drug targeted therapies in leukemia.
Zhu QS, Xia L, Mills GB, Lowell CA, Touw IP, Corey SJ. G-CSF induction of reactive oxygen species involves the Lyn-PI 3kinase-Akt pathway and is increased in cells expressing a truncated G-CSF Receptor associated with acute myeloid leukemia. Blood, 107:1847-1856, 2006.
Chen C, Huang X, Atakilit A, Zhu QS, Corey SJ, Sheppard D. The integrin a9b1 contributes to granulopoiesis by enhancing granulocyte colony stimulating factor receptor signaling. Immunity 25:895-906, 2006.
Wang L, Kurosaki T, Corey SJ. Engagement of the B cell antigen receptor activates STAT through Lyn in a Jak-independent pathway. Oncogene 26:2851-2859, 2007.
Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer. 7:118-29, 2007.
Hartig SM, Ishikura S, Hicklen RS, Feng Y, Blanchard EG, Voelker KA, Pichot CS, Grange RW, Raphael RM, Klip A, Corey SJ. The F-BAR protein CIP4 promotes GLUT4 endocytosis through bidirectional interactions with N-WASp and Dynamin-2. J Cell Sci. 122:2283-91, 2009.
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View Publications by Seth Corey listed in the National Library of Medicine (PubMed). |
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