M. Merced Malabanan, PhD. - Postdoctoral Fellow
Biochemical discovery of novel nuclear PIP3 readers, writers and erasers.
Hometown - Batangas, Philippines
B.S. Chemistry University of the Philippines (Diliman)
B.S. Food Technology University of the Philippines (Diliman)
Ph.D. Medicinal Chemistry University at Buffalo (John Richard)
See Merced's Publications on PubMed
Phosphoinositide phospholipids (PIPs) drive cancer by functioning as interaction surfaces for oncogenic proteins at cytoplasmic membranes. However, PIPs in the nucleus exist outside membranes, bound to unidentified nuclear proteins. Over 40% of nuclear PI(4,5)P (PIP2) and 80% of nuclear PI(3,4,5)P3 (PIP3) in mammalian cells can exist in this non-membrane state4—yet almost nothing is known about the identity, function or regulation of these protein/PIP complexes. Without understanding nuclear PIP function a huge hole exists in the complete picture of how these powerful signaling phospholipids promote oncogenesis.
We discovered that nuclear PIPs are bound by the NR5A1 nuclear receptor; a transcription factor expressed in the adrenals and gonads. PIP3 activates, while PIP2 represses NR5A1 function in transcription. We solved the crystal structures of many NR5A1/PIP complexes, which demonstrate that NR5A1 is a rigid scaffold, exposing the PIP headgroup to solvent .
This structural format of nuclear PIP led to two discoveries by our group: First, that lipid signaling enzymes have access to PIPs bound by NR5A1: The lipid phosphatase PTEN and a little known PI3-kinase called “Inositol Polyphosphate Multi-Kinase” (IPMK) modify PIPs bound to NR5A1, regulating NR5A1 function. The second discovery is that the PIP headgroup acts mechanistically as a novel molecular docking surface, akin to PIP function in membranes. We have now used proteomics to identify Pleckstrin Homology (PH)-domain containing proteins that regulate NR5A1. Thus, the data suggest that PH-domains act as nuclear PIP3 readers, while IPMK is a nuclear PIP3 writer and PTEN is a nuclear PIP3 eraser.
The hypothesis tested here is these reader, writer and eraser functions are broad paradigms that regulate proliferation of PTEN-dependent cancers (glioblastoma, hepatocellular carcinoma, prostate and endometrial cancer cells). These mechanisms drive proliferation at membranes, but we ask if similar mechanisms occur in the cancer cell nucleus. We test this hypothesis by identifying candidates regulated by each principle, then validate that those candidates regulate proliferation of relevant cancer cell lines in a PTEN enzyme-dependent manner.