Hirschberg Memorial Chair in Pancreatic Cancer Research
Director, UCLA: Digestive Diseases Research Center
Distinguished Professor of Medicine
Vatche and Tamar Manoukian Division of Digestive Diseases
David Geffen School of Medicine at UCLA
Dr. Rozengurt discovered that neuro-hormonal signals (e.g., peptides of the bombesin family) which act as molecular messengers in a rich network of information exchange throughout the organism via GPCRs, are potent cellular growth factors for multiple cell types in culture, including intestinal and pancreatic epithelial cells and function as autocrine/paracrine mitogens for human cancer cells. He studies the transmission of the neuro-hormonal signal from surface receptors to the nucleus along a number of transduction pathways, typically protein kinase cascades, that act in a synergistic and combinatorial fashion to regulate gene-regulatory networks leading to cell migration and proliferation. In the course of this work, he reported on the cloning and expression analysis of a novel protein kinase termed protein kinase D (PKD). PKD is directly activated by the potent tumor promotors of the phorbol ester family and also is part of a novel phosphorylation cascade downstream of protein kinase C (PKC). Research activities in this area include a detailed mutational analysis to define the contribution of different domains of PKD to its regulation, modulation of its expression to determine the role of PKD in cell regulation and development of animal models with over-expression or under-expression of PKD in the epithelial cells of the digestive system. In addition to serine/threonine protein kinase cascades, his studies demonstrated that neuropeptides also stimulate a rapid increase in the tyrosine phosphorylation of multiple substrates including focal adhesion kinase (FAK), paxillin, and Crk-associated substrate (CAS). These proteins localize at focal adhesion plaques and are implicated in cell migration, proliferation, and transformation. The signals converge on the transcriptional co-activators YAP and TAZ, which are emerging as potent oncogenes in pancreatic cancer. The work of Dr. Rozengurt is dissecting the molecular mechanisms by which neuro-hormonal agonists and growth factors induce these downstream pathways in intestinal and pancreatic epithelial cancer cells and is elucidating the role of these pathways in cell migration, proliferation and cancer. This work is also identifying inhibitors that block the signaling network at different steps and thus provides novel approaches for the treatment of proliferative diseases of the digestive system.