# Molecular Mechanisms of Cell Signaling

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $659,856

## Abstract

Summary/Abstract
 The overall vision of our research is to gain a comprehensive understanding of the
molecular mechanisms driving the function of a major brake to cell survival signaling, protein
kinase C (PKC), and its negative regulator, the PH domain Leucine-rich repeat Protein
Phosphatase (PHLPP). The PKC family has been intensely investigated in the context of cancer
since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters.
This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced
tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades
of research. In 2015 we reversed a major paradigm by showing that PKC generally suppresses,
rather than enhances, oncogenic signaling. This proposal aims to 1] understand the downstream
substrates and molecular mechanisms by which PKC isozymes brake oncogenic signaling and 2]
establish ways to restore PKC in cancer. Furthermore, we aim to understand the regulatory
mechanisms of its negative regulator, PHLPP, which we discovered in a targeted search for a
phosphatase that would dephosphorylate a conserved site on PKC and related kinases such as
Akt. PHLPP functions both as a tumor suppressor and as an oncogene and whereas much is
known about its substrates, downstream signaling pathways, and function, comparatively little is
known about its own regulatory mechanisms. This proposal aims to understand the structure and
regulatory mechanisms of PHLPP in order to inhibit target-specific roles of PHLPP, especially as
a way to restore PKC. The overarching challenge of the proposed research is to fill gaps in our
knowledge of the molecular mechanisms governing the regulation of, and signaling by, PKC and
PHLPP in order to leverage this understanding to develop effective therapies when these
mechanisms are disrupted in disease.

## Key facts

- **NIH application ID:** 10415752
- **Project number:** 2R35GM122523-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ALEXANDRA C. NEWTON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $659,856
- **Award type:** 2
- **Project period:** 2017-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415752

## Citation

> US National Institutes of Health, RePORTER application 10415752, Molecular Mechanisms of Cell Signaling (2R35GM122523-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415752. Licensed CC0.

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