# Identification of the growth-promoting PKD/YAP axis as a novel target for the statins in intestinal epithelial cells.

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

The sequential proliferation, lineage-specific differentiation, migration and death of the epithelial
cells of the intestinal mucosa is a tightly regulated process modulated by a broad range of
regulatory peptides, neurotransmitters, bioactive lipids and differentiation signals. Many of these
stimuli act through heptahelical G protein-coupled receptors (GPCRs). Despite their
fundamental importance, the intracellular signal transduction mechanisms involved remain
incompletely understood. Protein kinase D (PKD) is emerging as a key node in GPCR signaling
and consequently the understanding of PKD regulation and function in intestinal epithelial cells
is of intense interest and potential impact. The highly conserved Hippo/YAP/TAZ pathway is
also attracting strong attention as a key regulator of organ-size, tissue regeneration,
carcinogenesis and GPCR signaling. Based on our preliminary results, we identified a novel
crosstalk between PKD and YAP that plays a critical role in promoting intestinal epithelial cell
proliferation. Further preliminary results demonstrate that FDA-approved statins act as potent
inhibitors of GPCR/PKD-induced YAP-induced transcription and DNA synthesis in intestinal
epithelial cells. Statins also abrogated enteroid formation in vitro and prevented regeneration of
colon mucosa after injury. Consequently, our central hypotheses are: 1) PKD/YAP/TAZ
signaling plays a vital role in promoting the proliferation of intestinal epithelial cells including
progenitor/stem cells and 2) statins restrain intestinal epithelial cell proliferation by targeting the
PKD/YAP/TAZ axis in these cells. An important translational corollary is that the widely used
drugs of the statin family provide a novel strategy in the chemoprevention of colorectal (CRC)
and IBD-related CRC through inhibition of the growth-promoting PKD/YAP/TAZ axis. Three
Specific Aims are proposed: SPECIFIC AIM 1: Identify the mechanism(s) by which the lipid-
lowering drugs of the statin family target signaling through the PKD/YAP axis in intestinal
epithelial cells; SPECIFIC AIM 2: Characterize the impact of statin-induced inhibition of the
PKD/YAP/TEAD pathway on the proliferation of intestinal epithelial cells in vivo, including
progenitor and Lgr5+ intestinal stem cells and enteroids in 3 D cultures in vitro; SPECIFIC AIM
3: Determine the role of the statin-sensitive PKD/YAP/TEAD axis in intestinal epithelial cell
regeneration and carcinogenesis. We anticipate that the outcome of this proposal will provide a
robust rationale for implementing innovative therapeutic interventions targeting the PKD/YAP
signaling axis in proliferative diseases of the digestive system, including CRC and IBD-
associated CRC in US veterans as well as in the US population at large.

## Key facts

- **NIH application ID:** 9933785
- **Project number:** 5I01BX003801-03
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** JUAN ENRIQUE ROZENGURT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933785

## Citation

> US National Institutes of Health, RePORTER application 9933785, Identification of the growth-promoting PKD/YAP axis as a novel target for the statins in intestinal epithelial cells. (5I01BX003801-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9933785. Licensed CC0.

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