# The study of the interfacial catalysis and therapeutic potential of PTEN- L

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $44,436

## Abstract

Project Summary
PTEN, a key member of the PI3K pathway, exerts its main effect as a tumor suppressor by directly antagonizing
the activity of PI3K as an interfacial lipid phosphatase, via dephosphorylating membranous PIP3, resulting in
lower AKT activation. Expression of PTEN is lost in many cancer types, including breast, prostate and
glioblastoma, resulting in heightened AKT activity, which favors cell growth. Recent work in the Parsons lab led
to the discovery of PTEN-L, a secreted PTEN translational isoform, which can re-enter cells and dephosphorylate
PIP3 in the recipient cells. Previous studies from the Parsons group and others have indicated that exogenous
PTEN-L can enter tumor cells in PTEN null xenograft models and cause tumor regression and attenuation of
PI3K signaling. These works highlight the great potential for PTEN-L to be used as a targeted therapy for patients
with tumors bearing loss of PTEN. Although PTEN-L shares all domains of PTEN, including the phosphatase
domain, C2 domains, and the C-tail, PTEN-L also has an additional 173 amino acids at the N-terminus, the
function of which is still under investigation. Both PTEN and PTEN-L can be found in the cytoplasm and at
membranes but must be recruited to membranes in order to dephosphorylate PIP3. Published work indicates
that the N-terminal extension of PTEN-L, namely the membrane binding helix (MBH) domain, causes increased
affinity for the membrane with partially diminished phosphatase activity. The goal of this project is to study the
interfacial catalysis of PTEN-L in order to determine which PTEN-L domains are required for its phosphatase
activity against membranous PIP3 and determine the success of purified PTEN-L with alterations to the native
domains in treating tumors with aberrant PI3K signaling. In the first aim, we will determine the domains of PTEN-
L that are important for membrane localization and its subsequent lipid phosphatase activity; both functions are
vital for dephosphorylation of membranous PIP3. To test the requirement of the domains, we will mutate the
membrane localization domains of PTEN-L. We will test the effects of these mutants in PTEN null cells on
downstream PI3K signaling and localization to endogenous membranes in vitro and using biochemical assays.
In the second aim, we will determine whether exogenous PTEN-L domain mutant proteins can be effective in
treating cancer with aberrant PI3K signaling and whether these alterations to PTEN-L domains will improve
therapeutic efficacy. We will first test the ability of the domain mutants to suppress cell growth in PTEN null cells
in vitro. We will determine efficacy of purified PTEN-L domain mutants that retain growth suppression by
measuring downstream PI3K signaling and growth rates of treated PTEN null cell lines, and through the use of
xenograft and allograft models of PTEN null cancers. Next, we will determine whether any tested exogenous
PTEN-L mutant proteins have favorable pharmacokinetics, ...

## Key facts

- **NIH application ID:** 10179332
- **Project number:** 5F31CA243259-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kaitlyn Bosch
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $44,436
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179332

## Citation

> US National Institutes of Health, RePORTER application 10179332, The study of the interfacial catalysis and therapeutic potential of PTEN- L (5F31CA243259-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10179332. Licensed CC0.

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