Signal Transduction GI Cancer / Rozengurt Laboratories

Dr. Enrique Rozengurt, director of CURE: Digestive Diseases Research Center, is also director of the Signal Transduction Gastrointestinal Cancer Laboratories. His current focus is on signal transduction pathways leading to proliferation in normal and cancer cells.

The research activities promote the identification of extracellular factors and intracellular signal transduction pathways that stimulate cells to divide. For example, Dr. Rozengurt discovered that neuropeptides (peptides of the bombesin family - found in the central and peripheral nervous system of amphibians) that act as molecular messengers in a rich network of information exchange throughout the organism are potent cellular growth factors for multiple cell types in culture and function as autocrine/paracrine mitogens (chemical cells that induce cell division) for human cancer cells.

He studies the transmission of the neuropeptide 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 promote cell proliferation. His work revealed that regulatory peptides trigger a complex set of molecular responses and specific protein kinase cascades including kinase C and A, mitogen-activated protein kinases (MAPKs) and mTORC1/p70 S6 ribosomal protein kinase.

Recently, he reported on the cloning and expression analysis of a novel protein kinase termed protein kinase D (PKD), the founding member of a novel protein kinase family. PKD is directly activated by phorbol esters (organic tumor promoters) and also is part of a novel phosphorylation cascade downstream of PKC. Research activities in this area include a detailed mutational analysis to define the contribution of different domains of PKD to its regulation and function and to modulate its expression to determine its role in cell regulation.

In addition to serine/threonine protein kinase cascades, Dr. Rozengurt's 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, which localize at focal adhesion plaques, are implicated in cell migration, proliferation, and transformation.

More recently, Dr. Rozengurt is applying his expertise in signal transduction to the identification of novel crosstalk mechanisms in signaling networks. Positive points of interaction in the network are being identified as novel targets for therapeutic intervention in cancer cells, with a focus on colon and pancreatic epithelial cells.

In conclusion, his work has dissected molecular mechanisms by which growth-promoting factors induce downstream pathways, including protein phosphorylation cascades, and is elucidating the role of these pathways in normal and abnormal cell proliferation.


Key investigators

  • Enrique Rozengurt, DVM, PhD, AGAF, FRC Path (UK)
  • James Sinnett-Smith
  • Steven H. Young, PhD

Funding

  • P30 DK41301 (PI) CURE: Digestive Diseases Research Center, 12/01/14-11/30/19
  • R01 DK100405 (PI) Gastrointestinal Peptide Signaling through PKC/PKD 06/01/14-05/30/19
  • R01 DK098447 (PI Sternini), Extragustatory Functions of Bitter Taste Receptors, 04/15/15-03/31/19
  • Connie Frank and Evan Thompson Program for Collaborative Transplantation Research (PI Reed; Co-PI Rozengurt), YAP/TAZ axis is a novel pathway in HLA antibody-induced endothelial cell proliferation and an innovative mechanism by which statins prevent transplant rejection and transplant vasculopathy, 07/01/18-06/30/21
  • 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, 07/01/18-06/30/22
  • Roland Hirshberg Endowed Chair in Translational Pancreatic Cancer Research.

Current research projects

  • CURE: Digestive Diseases Research Center (CURE; DDRC)
    • Dr. Rozengurt is director of the CURE: DDRC, supported by NIDDK via a center grant mechanism. The center provides an optimal environment for cooperation and collaboration among its investigators, who have had a major impact on mucosal biology and on peptic ulcer diseases, and has a major impact upon expanded research areas in gastroenterology, including signal transduction mechanisms in the digestive system. The CURE: DDRC is also the major source of Pilot and Feasibility Study grants for young investigators and offers a forum to present and discuss novel findings in its conference program.
  • PKD1 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) edentify 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.

Key publications - Full list on PubMed

  1. Chang HH, Moro A, Chou CEN, Dawson DW, French S, Schmidt AI, Sinnett-Smith J, Hao F, Hines OJ, Eibl G, Rozengurt EMetformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse ModelSci Rep, 2018 12; 8(1):5899
  2. Chang JK, Ni Y, Han L, Sinnett-Smith J, Jacamo R, Rey O, Young SH, Rozengurt EProtein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localizationJ. Biol. Chem. 292: 9523-9539, 2017. PMC5465480
  3. Hao F, Xu Q, Zhao Y, Stevens JV, Young SH, Sinnett-Smith J, Rozengurt EInsulin Receptor and GPCR Crosstalk Stimulates YAP via PI3K and PKD in Pancreatic Cancer Cells Mol Cancer Res. 15:929-941, 2017.
  4. Wang J, Sinnett-Smith J, Stevens JV, Young SH, Rozengurt EBiphasic 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., 291: 17988-18005, 2016. PMC5016186
  5. Wang J, Han L, Sinnett-Smith J, Han LL, Stevens JV, Rozengurt N, Young SH, Rozengurt EPositive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser552Am J Physiol Cell Physiol: 310: C542-557, 2016 PMC4824155
  6. Soares HP, Ming M, Mellon M, Young SH, Han L, Sinnet-Smith J, Rozengurt EDual PI3K/mTOR inhibitors induce rapid over-activation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2Mol Cancer Ther 14: 1014-1023, 2015. PMC4394038
  7. Rozengurt E, Soares HP, Sinnet-Smith J. Suppression of Feedback Loops Mediated by PI3K/mTOR Induces Multiple Overactivation of Compensatory Pathways: An Unintended Consequence Leading to Drug ResistanceMol Cancer Ther 13: 2477-2488, 2014. PMC4222988
  8. Soares HP, Ni Y, Kisfalvi K, Sinnett-Smith J, Rozengurt EDifferent patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cellsPLoS One. 8:e57289, 2013. PMC3578870
  9. Rey O, Chang W, Bikle D., Rozengurt N, Young SH, Rozengurt ENegative crosstalk between the calcium-sensing receptor and β-catenin signaling systems in colonic epitheliumJ. Biol. Chem. 287: 1158-1167, 2012. PMC3256874
  10. Sinnett-Smith J, Rozengurt N, Kui R, Huang C, Rozengurt EProtein Kinase D1 Mediates Stimulation of DNA Synthesis and Proliferation in Intestinal Epithelial IEC-18 Cells and in Mouse Intestinal CryptsJ. Biol. Chem. 286: 511-20, 2011. PMC3013011
  11. Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between Insulin/IGF-1 and GPCR Signaling Systems: A Novel Target for the Anti-diabetic Drug Metformin in Pancreatic CancerClin Cancer Res. 16: 2505-11, 2010. PMC2862089

Past GI/STAR research fellows

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

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