The role of SHIP's C2 and PH domains in regulating hematopoietic cell growth and function

Various cancers and inflammatory diseases occur as a result of inappropriate activation of the body’s blood-forming hematopoietic cells. Normally, cellular activation, growth and survival in hematopoietic cells are regulated by the phosphoinositide 3-kinase (PI3K) pathway, which drives a wide range of cellular processes. Keeping tight control on this pathway is SHIP (SH2 domain-containing inositol 5' phosphatase), a counteracting enzyme that inhibits PI3K action. SHIP is found only in blood and immune system cells and is the major restraining mechanism in these cell types. Loss or impaired activity of SHIP – in effect, removing the brakes on the PI3K pathway – has been implicated in certain leukemias and in inflammatory disease. Recently, researchers discovered small molecules that are capable of enhancing SHIP activity, resulting in both the inhibition of immune cell activation and the death of hematopoietic cancer cells. This represents a previously unknown mode of regulating SHIP enzyme activity. Andrew Ming-Lum is determining the significance of this novel type of regulation of SHIP function. Using cell lines and mouse models, he is focusing on a previously unrecognized domain on the enzyme, upon which the small molecules are believed to act. These studies will provide greater insight into how this mechanism affects the function, growth and survival of hematopoietic cells. It will also provide insight into the dysregulation that occurs in certain cancers and inflammatory diseases.