Antonio Di Cristofano, Ph.D.

Phosphatidylinositol-3-kinase (PI3K) is a crucial mediator of receptor-initiated signaling cascades, catalyzing the conversion of phosphatidylinositol (4,5)-diphosphate (PIP-2) into phosphatidylinositol (3,4,5)-triphosphate (PIP-3).  Among the major effectors of PI3K is the AKT kinase, which is activated upon PIP-3-mediated membrane recruitment and, in turn, phosphorylates an ever-growing list of target proteins, regulating key processes such as proliferation, survival, cell size, genome stability, and mRNA translation.  This cascade is counteracted by the PTEN tumor suppressor, which opposes PI3K activity by dephosphorylating PIP-3 to PIP-2.  Heterozygous mutation of PTEN causes Cowden disease, a dominant genetic syndrome whose characteristics include an increased risk for developing breast, endometrial and thyroid cancer.  Somatic deletions, mutations and epigenetic inactivation of PTEN have been identified in a large fraction of tumors (endometrial, glioblastoma, prostate, thyroid, melanoma), placing PTEN among the most commonly mutated genes in human cancer. 

The central focus of my laboratory is the identification and characterization of the specific biological processes and transduction pathways that are controlled by the PI3K/PTEN/AKT cascade.  In particular, we utilize in vivo and ex vivo approaches to identify and deconstruct the signaling cascades altered during early neoplastic transformation of epithelial tissues, and to understand through which signaling nodes the PI3K cascade intersects with other growth-promoting pathways.