It is established that the phosphatase and tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is mutated in a variety of cancers, often resulting in PTEN loss of function. At cell membranes, PTEN opposes the activity of phosphatidylinositol 3-kinases (PI3Ks), which generate the signaling lipid PIP3. PI3K activation leads to the stabilization of key cell signaling complexes at the membrane via PH-domain mediated interactions with PIP3. This complex formation is required for proper signal transduction to occur; however, upregulated PI3K activity (overproduction of PIP3) is associated with several cancer types . However, drugs targeting membrane PI3Ks have widely failed. Our lab studies a nuclear PI3K called IPMK (inositol polyphosphate multikinase) that converts PIP2 to PIP3 while bound to a transcription factor, NR5A1. IPMK conversion of PIP2 to PIP3 while bound to NR5A1 increases the expression of NR5A1 target genes. PTEN, in an opposing manner, is able to dephosphorylate PIP3 to PIP2, causing repression of NR5A1 target genes. I hypothesize that a close NR5A1 homolog, NR5A2, is regulated by IPMK in the same way and that PIP3 stabilizes transcriptional complexes via PH-domain mediated interactions similar to its role at cell membranes. If proven, these results would implicate IPMK as a cancer drug target.
Graduate Student, Blind laboratory
BA, Fisk University (2015)