Membrane ‘neighborhood’ helps transporter protein regulate cell signaling

(MEMPHIS, Tenn. – December 5, 2025) When a cell receives a message from outside, it generates a molecule called cyclic AMP (cAMP) to relay this message. To ensure the signal reaches the correct effector without triggering pathways accidentally, cAMP levels must be maintained around their point of origin and at the right level. ABCC4, a protein that transports cAMP out of cells and also contributes to drug resistance, helps with this local control. Yet, how ABCC4 is held in place at the right spot to perform these functions was not clear. Scientists at St. Jude Children’s Research Hospital revealed that global elevation of cAMP levels promotes ABCC4 localization to the plasma membrane and stabilizes ABCC4, forming a protein “neighborhood” that locks the transporter in place. They identified a key contributor to this protein neighborhood, SCRIB, and found that a known ABCC4 inhibitor disrupts the network by breaking the interaction between SCRIB and ABCC4. These results uncover a previously unappreciated protein network and shine new light on how this vital class of transporters can be regulated. The findings were published this week in Nature Communications.

When a signal from outside a cell is received, cAMP relays that signal from the cell membrane to a waiting effector protein, such as protein kinase A. To ensure the signal stays where it needs to be and avoid widespread effects, the ABCC4 transporter moves to where the signal is and pumps cAMP out of the cell. However, the transporter needs to be stabilized at the cell membrane to do this, but the researchers were unclear how this happens.

Corresponding author John Schuetz, PhD, St. Jude Department of Pharmacy & Pharmaceutical Sciences, and his team explored ABCC4 stabilization. “We examined ABCC4 with an inhibitor, Ceefourin-2, and noticed something strange: At concentrations that should completely inhibit the protein’s activity, we couldn’t see any demonstrable stabilization,” Schuetz says. “So, we wondered if it’s actually affecting a network of proteins and explored both close and distant interactions.”

Neighborhood locks ABCC4 in place

They found that interactions between ABCC4 and its neighbors through protein sections called PDZ motifs holds the transporter in place. The PDZ motifs find other PDZ domain-containing proteins and acts like sticky tape. This interaction restricts ABCC4’s movement at the cell membrane, locking it in place so it can maintain cAMP levels to function properly. Loss of the PDZ motif destabilized ABCC4 protein interactions and affected cAMP transport by disrupting the PDZ-dependent network. They further found that a known ABCC4 inhibitor disrupted ABCC4 interaction with SCRIB, the most significant network member, causing ABCC4 to diffuse, thus diluting the cAMP signaling effect throughout the cell.

These results offer a novel route to regulating a vital ABC transporter, not just by targeting the active site of the protein, but the membrane neighborhood around it. The ability to target these networks opens a new therapeutic opportunity for modification of cAMP signaling and ABC transporters.

“We’d like to use other known inhibitors to see if they act via a similar mechanism. This work implies SCRIB is the most important, but there could be others,” Schuetz says. “This demonstrates that many transport proteins aren’t isolated — they’re connected to a network.”

Authors and funding

The study’s first authors are Jingwen Zhu and Sabina Ranjit, St. Jude. The study’s other authors are 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, St. Jude.

The study was supported by the National Institutes of Health (R01 CA194057, CA194206, P30 CA21745, CA21865, 5R01DK080834, P30 CA021765, and CA96832), and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.

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