Digestive Diseases Research

Rozengurt Laboratory

Enrique Rozengurt, DVM, PhD, AGAF

Signal transduction GI cancer

Key investigator

  • Enrique Rozengurt, DVM, PhD, AGAF

Funding

  • NIH P01CA236585 - Role: Project Leader; Project 2 Chemoprevention and mechanisms of obesity-promoted pancreatic adenocarcinoma, 05/01/2020 – 04/30/2025
  • NIH R21CA258125 - (MPI: Rozengurt; Eibl) Interaction between chronic stress and obesity in pancreatic cancer progression. 05/01/2022 – 04/30/2024    
  • NIH R21AI156592 - (MPI: Reed, Rozengurt) Targeting YAP with statins to prevent antibody-mediated transplant rejection, 012/18/2020 – 11/30/2023
  • VA Merit Review I01 BX003801 - (PI) Identification of the growth-promoting PKD/YAP axis as a novel target for the statins in intestinal epithelial cells, 07/01/18-06/30/23
  • Roland Hirshberg Endowed Chair in Translational Pancreatic Cancer Research

Current research projects

  • KD1 Signaling and Crosstalk Mechanisms in Intestinal Epithelial Cell Regulation
    • Aims: 1) characterize the role of PKD1 signaling in intestinal epithelial cell proliferation in vivo and in stem cell-derived intestinal organoids, 2) characterize crosstalk mechanisms between PKD1 and β-catenin signaling systems in intestinal epithelial cells, and 3) identify a novel mechanism of PKD1 regulation through PAK-mediated PKD1 phosphorylation at the N-terminal residue Ser203.
  • The Hippo/YAP/TAZ Pathway in the Regulation of Intestinal, Pancreatic and Endothelial Cell Proliferation
    • Aims: 1) Characterize the role of the Hippo/YAP/TAZ pathway in the control of proliferation of intestinal and pancreatic epithelial cells, and 2) Identify the signal transduction pathways that mediate the regulation of YAP expression, localization and phosphorylation in these cells.
  • Chemoprevention of Pancreatic Cancer with Anti-Diabetic Agents
    • The aim of this project is to characterize the chemo-preventive effects of metformin on the progression of PanINs using the conditional KrasG12D model subjected to standard or a high fat, high calorie diet (HFCD). This animal model system recapitulates the lesions seen in the human disease, namely  pancreatic pre-neoplatic lesions followed by their conversion of carcinoma in situ to invasive ductal pancreatic carcinoma.

Future research directions

  • The future directions are an extension of the current research: Signal transduction mechanisms through protein kinase cascades; elucidation of crosstalk mechanism between Protein kinase D (PKD) and downstream gene-regulatory programs; novel approaches in the therapy and prevention of GI cancers, especially pancreatic cancer.

In the news

  • Chronic stress and obesity combine to accelerate pancreatic cancer development and growth, study finds (2025)
    • A new study led by UCLA investigators suggests that chronic stress and an unhealthy diet may combine to fuel the early development of pancreatic cancer, shedding light on how lifestyle factors contribute to one of the deadliest malignancies. The findings suggest that stress hormones and obesity-related hormones activate key cancer-promoting pathways, potentially accelerating the onset of pancreatic cancer. One possible solution, researchers suggest, is to explore the use of existing medications to reduce this risk. Since β-adrenergic receptors play a crucial role in stress-related cancer growth, commonly used beta-blockers, which are used to treat high blood pressure, could be repurposed to help mitigate these effects. Enrique Rozengurt, DVM, PhD, distinguished professor of medicine, was a senior author on this study published in Molecular Cancer Research. James Sinnet-Smith also contributed to the paper. Read full article in UCLA Health News & Insights
  • Dr. Rozengurt honored as a ScholarGPS Highly Ranked Scholar (May 2024)
    • ScholarGPS celebrates Highly Ranked Scholars™ for their exceptional performance in various fields, disciplines and specialties. Dr. Rozengurt’s prolific publication record, the high impact of his work and the outstanding quality of his scholarly contributions have placed him in the top 0.05% of all scholars worldwide according to ScholarGPS’s analytic tools. Dr. Rozengurt is the only UCLA scientist to be identified as Highly Ranked Scholar in molecular and cell biology. According to ScholarGPS metrics, Dr. Rozengurt ranks number one in tyrosine phosphorylation, number two in DNA synthesis and phorbol esters and number three in cell physiology! Dr. Rozengurt is a distinguished professor of medicine and Hirschberg Memorial Chair in Pancreatic Cancer Research. View his scholar profile and ranking

Key publications - Full full list on PubMed

  1. Sternini C, Rozengurt E. Bitter taste receptors as sensors of gut luminal contents(Link is external). Nature Reviews Gastroenterology & Hepatology. 28 October 2024
  2. Benhammou JN, Qiao B, Ko A, Sinnett-Smith J, Pisegna, Rozengurt E. Lipophilic statins inhibit YAP co-activator transcriptional activity in HCC cells through Rho-mediated modulation of the actin cytoskeleton. American Journal of Physiology-Gastrointestinal and Liver Physiology. June 27, 2023
  3. Sinnett-Smith J, Torres-Marquez ME, Chang JK, Shimizu Y, Hao F, Martin MG, Rozengurt E. Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. American Journal of Physiology- Cell Physiology. 324:C807-C820, 2023
  4. Anwar T, Sinnett-Smith J, Jin YP, Reed EF, Rozengurt E. Lipophilic Statins Inhibit YAP Nuclear Localization, Coactivator Activity, and Migration in Response to Ligation of HLA Class I Molecules in Endothelial Cells: Role of YAP Multisite Phosphorylation. Journal of Immunology.  210:1134-1145, 2023
  5. Ako S, Teper Y, Ye L, Sinnett-Smith J, Hines OJ, Rozengurt E, Eibl, G. Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar to Ductal Metaplasia of Pancreatic Cells. Advances in Gastroenterology and Hepatology.1: 640-651, 2022
  6. Jin YP, Nevarez-Mejia J, Terry AQ, Sosa RA, Heidt S, Valenzuela NM, Rozengurt E, Reed EF. Cross-Talk between HLA Class I and TLR4 Mediates P-Selectin Surface Expression and Monocyte Capture to Human Endothelial Cells. Journal of Immunology. 209: 1359-1369, 2022
  7. Sinnett-Smith J, Anwar T, Reed EF, Teper Y, Eibl G, Rozengurt E. Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy. Molecular Cancer Therapeutics. 21: 1652-1662, 2022
  8. Anwar T, Sinnett-Smith J, Jin YP, Reed EF, Rozengurt E. Ligation of HLA Class I Molecules Induces YAP Activation through Src in Human Endothelial Cells. Journal of Immunology. 205:1953-1961, 2020
  9. Chang HH, Moro A, Chou CEN, Dawson DW, French S, Schmidt AI, Sinnett-Smith J, Hao F, Hines OJ, Eibl G, Rozengurt E. Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model. Sci Rep, 2018 12; 8(1):5899
  10. Hao F, Xu Q, Zhao Y, Stevens JV, Young SH, Sinnett-Smith J, Rozengurt E. Insulin receptor and GPCR crosstalk stimulates YAP via PI3K and PKD in pancreatic cancer cells. Mol Cancer Res 2017;15: 929-41
  11. Chang JK, Ni Y, Han L, Sinnett-Smith J, Jacamo R, Rey O, Young SH, Rozengurt E. Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization. J Biol Chem 2017; 292:9523-39
  12. Wang J, Sinnett-Smith J, Stevens JV, Young SH, Rozengurt E. Biphasic regulation of Yes-associated Protein (YAP) cellular localization, phosphorylation and activity by G protein-coupled receptor agonists in intestinal epithelial cells: a novel role for protein kinase D (PKD). J Biol Chem 2016;291: 17988-18005

Recent reviews

  1. Rozengurt E, Eibl G. Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance. Cancers 13: 5126, 2021
  2. Eibl G, Rozengurt E. Obesity and Pancreatic Cancer: Insight into Mechanisms. Cancers 13: 5067, 2021

Past GI/STAR research fellows

  • Jihane N. Benhammou, MD, PhD
  • Terence Chiu, MD, PhD
  • Sushovan Guha, MD, PhD
  • J. Adrian Lunn, MD, PhD
  • Heloisa Soares, MD, PhD

About Dr. Rozengurt

Hirschberg Memorial Chair in Pancreatic Cancer Research
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 and neurotensin families) which act as molecular messengers in a rich network of information exchange throughout the organism via G protein-coupled receptors (GPCRs), are potent cellular growth factors for multiple cell types. These include, fibroblasts, myofibroblasts, intestinal and pancreatic epithelial cells. He studies the transmission of the neuro-hormonal signal from surface receptors to the nucleus along several 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 discovery 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 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 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 transcription factor CREB and 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 targets and approaches for the treatment of proliferative diseases of the digestive system.