Recent studies conducted by researchers at the University of California San Diego have revealed that cells control cAMP/PKA signaling by creating liquid droplets that separate excess PKA catalytic subunits to prevent any harm. Certain types of cancer may prevent the formation of these liquid droplets, resulting in overactive signaling and the development of tumors. Healthy cells, on the other hand, effectively manage this process by forming liquid droplets to maintain normal cellular function.
Cells have the ability to respond to changes in their environment by sensing the outside world and sending commands to specific biomolecules in the right place to carry out the necessary response. This process helps keep the body healthy. However, if the message ends up in the wrong place at the wrong time, it can lead to diseases such as diabetes or cancer.
These routes that messages take inside a cell are known as signaling pathways. Cells use a small number of signaling pathways to respond to numerous external signals simultaneously, so it is crucial that these pathways are tightly regulated.Scientists at the University of California San Diego have discovered an unexpected method that cells use to regulate signaling pathways. They have observed that when there is an excess of messages within a cell, the messengers gather to form liquid droplets, isolating themselves and preventing any potential harm. The research findings were recently published in Molecular Cell.
Jin Zhang, Ph.D., a professor of pharmacology at UC San Diego School of Medicine and the senior author of the study, stated, “Liquid droplets organize cellular biochemical activities according to spatiotemporal regulation.”
The scientists focused on a key mechanism for controlling cell signaling pathways.The process of cellular communication involves the cAMP/PKA signaling pathway, which involves two main components: cAMP (cyclic adenosine monophosphate) and PKA (cAMP-dependent protein kinase). When the cell’s surface sends a signal to cAMP, it activates PKA. PKA then transmits the message to the appropriate domain, whether it is instructing a specific gene to produce more protein or stimulating an enzyme to regulate glucose levels in the blood.
However, the process is not as straightforward as it may seem. PKA delivers messages to numerous different domains. According to Zhang, “At one moment, PKA needs to be active on the plasma membrane. But the next moment, it needs to cSome molecules come off the plasma membrane and become active on the mitochondrial membrane. After ten minutes, they need to be in the nucleus to start the process of transcription.
To make things more complex, there are times when cells activate too much cAMP and PKA. When this happens, cell signaling becomes excessively active and unselective. Zhang explains, “Different microdomains control different functions. For example, if you want the cAMP level to be high around calcium channels but low 10 nanometers away, how does the cell achieve that? By regulating cAMP.” She continues, “The same goes for PKA. Normally, it is brought to specific domains by anchoring proteins. However, if the PKA activity is too high, it can spread throughout the cell.”If the concentration of cAMP is too high, it will activate domains it’s not supposed to be activating. This leads to a loss of specificity. This is why, according to the latest research, cells create liquid droplets to ensure that the correct message reaches the correct domain at the correct time. The scientists found that when too much cAMP and PKA were being turned on, cells formed the droplets using a subunit of PKA. This allowed the droplets to contain the excess cAMP and PKA and reduce non-specific signaling. In previous studies, it was found…In their study, the researchers discovered that Fibrolamellar Carcinoma (FLC), a rare form of liver cancer, inhibits the formation of liquid droplets, which leads to uncontrolled cell signaling. According to Zhang, the disappearance of these liquid droplets is a major factor in the hyperactive signaling that triggers tumorigenesis. FLC is a rare and destructive disease that primarily affects individuals under the age of 40 with healthy livers. The authors aim to explore whether other cancers also lead to a loss of liquid droplets and to uncover the molecular mechanisms behind this phenomenon. Their ultimate objective is to develop a molecular therapy for this type of cancer.eutic to treat Fibrolamellar Cancer (FLC) — “anything,” says Zhang, “that helps us address the unmet needs of FLC patients.”
The authors of this study include Julia C. Hardy, Emily H. Pool, Jessica G.H. Bruystens, Xin Zhou, Qingrong Li, Daojia R. Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L.C. Choi, Ha Neul Lee Dong Wang, Susan S. Taylor, Sohum Mehta, Jin Zhang at University of California San Diego and Stefan Strack at University of Iowa.
This work was supported by the National Institutes of Health and Fibrolamellar Cancer Foundation.
Journal Reference:
- Julia C. Hardy, Emily H. Po
- authors: Jessica G.H. Bruystens, Xin Zhou, Qingrong Li, Daojia R. Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L.C. Choi, Ha Neul Lee, Stefan Strack, Dong Wang, Susan S. Taylor, Sohum Mehta, Jin Zhang.
- Molecular determinants and signaling effects of PKA RIα phase separation. Molecular Cell, 2024; 84 (8): 1570 DOI: 10.1016/j.molcel.2024.03.002