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.
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.”