# Interactions of pleiotrophin with receptor type protein tyrosine phosphatase

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2021 · $277,269

## Abstract

Pleiotrophin (PTN) is a vital cytokine responsible for stimulating cell differentiation, neural development,
angiogenesis and hematopoietic stem cell maintenance. Although PTN is crucial to tissue regeneration after
injury, errant expression of the cytokine often leads to pathogenic conditions. Specifically, PTN is
overexpressed in a large number of cancers and reduction of PTN activity decreases the growth rates and
metastatic potentials of those cancers. This indicates PTN signaling maybe a valuable target for treating a
number of ailments. However, little is known about the structural mechanism of PTN signaling. We want to
investigate structural determinants that regulate PTN’s interactions with receptor-type protein tyrosine
phosphatase zeta (PTPRZ), a chondroitin sulfate (CS) proteoglycan and the receptor associated with PTN’s
mitogenic and angiogenic activities. Our hypothesis is that PTN’s two independent domains can cross link
PTPRZ by binding to their glycosaminoglycan chains or core proteins, resulting in PTPRZ auto-inhibition. We
want to confirm our model and investigate whether GAG-induced PTN oligomer is necessary in PTN signaling.
In our preliminary studies, we have determined PTN’s structure and showed PTN’s affinity for
glycosaminoglycan is dependent on the sulfation density and iduronate content of the glycan. We also showed
that the C-terminal tail of PTN, known to be crucial for PTPRZ signaling for unexplained reasons, is essential to
maintaining stable interactions with the type of CS found in PTPRZ, and that PTN binds to a segment of the
PTPRZ protein with even higher affinity than CS, thereby providing additional mechanisms for PTPRZ
crosslinking. We also showed that PTN oligomerization only happens in the presence of glycosaminoglycans
and the PTN oligomerization interface most likely involve both structural domains in PTN. Building on the
success of our preliminary studies, we want to further investigate structural mechanisms of PTN signaling.
Specifically, we propose to: 1) Determine structures of PTN-GAG complexes with a focus on oversulfated
dermatan sulfate, which can potentially be a potent PTN inhibitor. 2) Determine the oligomer structure of PTN
and engineer obligatory monomers of PTN to examine the role of PTN oligomers in its interactions with PTPRZ.
3) Determine the functional impact of PTN’s interactions with the protein component of PTPRZ and find other
PTN-binding sites in the PTPRZ core protein. These interactions could be a crucial part of PTN-PTPRZ
signaling, therefore modulation of PTN activity is not complete without considering such interactions. 4)
Investigate whether PTN’s activity is associated with its ability to crosslink proteoglycans using a novel model
proteoglycan system. This system will allow us to test whether crosslinking is dependent on the core protein of
PTPRZ and investigate the influence of glycan sulfation density and length on crosslinking and activity of PTN.

## Key facts

- **NIH application ID:** 10111525
- **Project number:** 5R01GM118518-05
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Xu Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $277,269
- **Award type:** 5
- **Project period:** 2017-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111525

## Citation

> US National Institutes of Health, RePORTER application 10111525, Interactions of pleiotrophin with receptor type protein tyrosine phosphatase (5R01GM118518-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111525. Licensed CC0.

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