# Regulation of Erythrocyte Function

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $448,996

## Abstract

Project Summary
Despite long held beliefs that the human erythrocyte is an “inert bag of hemoglobin”, many studies now reveal
that the human red blood cell (RBC) is sensitively regulated by a variety of stimuli, including O2 pressure,
mechanical deformation, multiple hormones and oxidative stress. We have shown recently that stimuli that
promote tyrosine phosphorylation of the major erythrocyte membrane protein, band 3 (a.k.a. SLC4A1, anion
exchanger, AE1), also induce erythrocyte membrane destabilization, leading in many cases to membrane
vesiculation and cell fragmentation. More detailed exploration of the mechanism underlying this membrane
destabilization has revealed that phosphorylation of the cytoplasmic domain of band 3 induces its
intramolecular docking with a highly atypical “SH2-like structure” within the membrane-spanning domain of
band 3, resulting in rupture of the band 3-ankyrin bridge that connects the membrane to its cytoskeleton (and
thereby promoting the aforementioned membrane destabilization). While this observation was at first
perplexing, upon subsequent discovery that tyrosine phosphorylation of band 3 does not occur in healthy
RBCs but is prominent in both sickle cells and malaria parasite-infected RBCs, we wondered whether the
phosphorylation-induced membrane destabilization might contribute to development of these diseases.
Follow-on studies revealed that inhibitors of band 3 tyrosine phosphorylation also inhibited: 1) the membrane
weakening required for egress of malaria parasites from their RBC hosts, resulting in termination of the
parasitemia, and 2) the membrane destabilization responsible for the intravascular hemolysis and release of
membrane microparticles that are reported to trigger vaso-occlusive events in sickle cell patients. Motivated by
these and other confirming observations, we have proposed in Aim 1 to characterize the phosphorylation
pathways that lead to band 3 tyrosine phosphorylation and membrane destabilization in both sickle cells and
malaria-infected RBCs. In Aim 2 we will use this information to design and evaluate inhibitors of these
pathway(s) for possible use as therapeutics for treatment of the two pathologies. In Aim 3 we will characterize
the phosphotyrosine binding properties of homologous “SH2-like structures” that we have found in 47 other
solute transporters of highly diverse functions and different evolutionary families. Because most of these
transporters have significant pathologies associated with their malfunctions (e.g. the serotonin, dopamine,
glutamate, glucose, and nucleoside transporters, etc.), elucidation of their mechanisms of regulation by
tyrosine phosphorylation should reveal new approaches for treatment of their associated diseases. Thus,
collectively, the information generated by the proposed studies will not only yield information that could lead to
treatments for malaria and sickle cell disease, but also for a variety of other human maladies caused by the
malfunction...

## Key facts

- **NIH application ID:** 10018035
- **Project number:** 5R01GM024417-41
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** PHILIP Stewart LOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,996
- **Award type:** 5
- **Project period:** 1977-07-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018035

## Citation

> US National Institutes of Health, RePORTER application 10018035, Regulation of Erythrocyte Function (5R01GM024417-41). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10018035. Licensed CC0.

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