Membrane Zone Supports Precise Cell Signaling by Stabilizing Transporter Proteins
(MEMPHIS, Tenn. – December 5, 2025) When external signals reach a cell, it generates a messenger called cyclic AMP (cAMP) to carry that message to the right target. To prevent accidental activation of unintended pathways, cAMP must stay near its production site and remain at the correct concentration. ABCC4, a transporter protein that moves cAMP out of cells and can also influence drug resistance, helps enforce this local control. Yet the mechanism that anchors ABCC4 at the proper location remained unclear. Researchers at St. Jude Children’s Research Hospital discovered that when global cAMP levels rise, ABCC4 is recruited to the plasma membrane and stabilized there, forming a molecular neighborhood that effectively pins the transporter in place. A key contributor to this neighborhood is SCRIB, and the team found that a known ABCC4 inhibitor disrupts the network by breaking the SCRIB–ABCC4 interaction. These findings reveal an unappreciated protein network that shapes how this essential transporter’s activity is regulated. The results were published recently in Nature Communications.
When a signal is received outside the cell, cAMP conveys that message from the cell surface to an awaiting effector, such as protein kinase A. To keep the signal confined and prevent widespread effects, the ABCC4 transporter relocates to the signal’s location and pumps cAMP out of the cell. However, ABCC4 must be stabilized at the membrane to function, and the exact process behind this stabilization was not fully understood.
Corresponding author John Schuetz, PhD, from the St. Jude Department of Pharmacy & Pharmaceutical Sciences, and colleagues investigated how ABCC4 is maintained at the membrane. “We studied ABCC4 in the presence of Ceefourin-2, an inhibitor, and observed an unexpected result: at concentrations that should completely block the transporter’s activity, there was no obvious stabilization,” Schuetz explains. “That led us to wonder whether ABCC4 sits within a broader network of interacting proteins and to examine both nearby and distant interactions.”
A membrane neighborhood that locks ABCC4 in place
The team found that ABCC4’s stability depends on interactions between its PDZ motifs and neighboring PDZ-domain proteins, which act like molecular glue. These connections limit ABCC4’s movement at the cell surface, keeping it anchored so the transporter can maintain local cAMP levels and signaling fidelity. Removing the PDZ motif weakened ABCC4’s protein interactions and disrupted cAMP transport by breaking the PDZ-dependent network. Crucially, the inhibitor Ceefourin-2 disrupted ABCC4’s association with SCRIB, the major network player, causing ABCC4 to diffuse and diluting the local cAMP signal across the cell.
These results point to a novel way to regulate a vital ABC transporter—not merely by inhibiting the transporter’s active site, but by targeting the surrounding membrane neighborhood that supports it. Targeting these protein networks could open new therapeutic avenues for modulating cAMP signaling and the function of ABC transporters.
“We’d like to test other known inhibitors to see if they work through a similar mechanism. This study suggests SCRIB plays a pivotal role, but other network members may also contribute,” Schuetz notes. “This work demonstrates that many transport proteins are not isolated actors but parts of interconnected networks.”
Authors and funding
The study’s first authors are Jingwen Zhu and Sabina Ranjit, from St. Jude. Additional authors include Anjaparavanda Naren (Cedars-Sinai Medical Center) and Tomoka Gose, Amanda Nourse, Vishwajeeth Pagala, Zuo-Fei Yuan, John Lynch, Yao Wang, Aaron Pitre, Rebecca Crawford, Junmin Peng, and Juwina Wijaya, all from St. Jude.
Funding came from the National Institutes of Health (grants listed: R01 CA194057, CA194206, P30 CA21745, CA21865, 5R01DK080834, P30 CA021765, CA96832) and the American Lebanese Syrian Associated Charities (ALSAC), St. Jude’s fundraising and awareness organization.
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