# Signal Transduction by Non-Transmembrane PTPs

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $529,389

## Abstract

Project Summary
Many important biological processes are regulated by protein-tyrosyl phosphorylation. Tyrosyl
phosphorylation, in turn, is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine
phosphatases (PTPs). Abnormal regulation of these pathways can lead to developmental defects
and diseases such as cancer. A complete understanding of cellular regulation by tyrosyl
phosphorylation requires defining the PTKs and PTPs involved and determining how they
interact. Such understanding may lead to the development of new drugs that selectively target
elements of these signaling pathways, agents that may be useful for the treatment of human
disease. The goal of our research program has been to delineate the mechanism of action of
non-transmembrane PTPs. During this MERIT award, we made major progress in
understanding the normal function and role in disease of SHP2, SHP1, and PTP1B. Over the
past year, we discovered a new pathway involving PTP1B, and its putative substrate, the
Moyamoya disease-associated AAA+ ATPase/E3 ligase RNF213, in the control of
α-ketoglutarate-dependent dioxygenase (aKGDD) activity, non-mitochondrial O2 consumption
(NMOC) and survival of HER2+ BC cells and at least other BC subtypes under hypoxic
conditions. Preliminary data suggest a model in which tyrosyl phosphorylation activates
RNF213, which has K6 E3-ubiquitin ligase activity, and may regulate cystine uptake,
intracellular redox tone, ascorbate levels and global αKGDD activity. We propose to elucidate
the molecular details of this pathway, and its relevance to HER2 tumorigenesis and to other
types of BC. We will ask how PTP1B regulates RNF213, how RNF213 controls αKGDDs/NMOC,
and how generally this pathway regulates hypoxia and tumorigenesis. Our results will provide
new insights into the hypoxia response, regulation of ubiquitylation by K6 ligases, control of the
αKGDDs, the possible therapeutic effects of PTP1B inhibitors and ascorbate, and Moyamoya
disease pathogenesis.

## Key facts

- **NIH application ID:** 9993312
- **Project number:** 5R01CA049152-30
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** BENJAMIN G. NEEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $529,389
- **Award type:** 5
- **Project period:** 1988-12-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993312

## Citation

> US National Institutes of Health, RePORTER application 9993312, Signal Transduction by Non-Transmembrane PTPs (5R01CA049152-30). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993312. Licensed CC0.

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