Centrosomes are small structures in cells with many essential functions, including roles in cell signaling and in organizing a cell's cytoskeleton. Centrosome dysfunction contributes to diseases like cancer and congenital developmental disorders - for which understanding what regulates centrosome function is key.
In a new study, Yale researchers have uncovered two proteins that play a role in this regulation, shedding light on centrosome-related disorders and revealing potential targets for treatment.
The findings were reported in the journal Current Biology.
The first protein that caught the researchers' attention is one known as PPP2R3C, first identified during a genome-wide screen, in which they mutated every gene in the genome to find those that affected the function of structures closely tied to centrosomes. Then researchers found that mutations in the PPP2R3C gene are linked to developmental syndromes. (Names of genes are written in italics.)
"We were intrigued by this connection to disease, and then by mining available data we started to develop an idea of what PPP2R3C's function might be in cells," said David Breslow, senior author of the study and an assistant professor of molecular, cellular, and developmental biology in Yale's Faculty of Arts and Sciences. "That got us excited about this protein."
Breslow and his colleagues observed that PPP2R3C gathered at centrosomes of typical, healthy cells, supporting the idea that it played a role in centrosome function. But as they dug further, they found that knocking out its gene had a wide range of effects: doing so killed some cells while others remained largely fine.
"We were trying to figure out why there was so much variation," said Breslow. "So we looked to see if there were other genes that might explain why knocking out PPP2R3C could be severe or inconsequential, and it turned out expression of a gene called MAP3K1 predicted this variability really well."
Upon further analysis, the researchers found that these two proteins, PPP2R3C and MAP3K1, have opposing roles at centrosomes. Breslow likened PPP2R3C to a brake and MAP3K1 to a gas pedal. Removing just the brake caused cells to die or to have major growth defects. But if they removed both proteins - both the brake and the gas pedal - cells remained functional.
Supporting the idea of these linked but opposing roles, mutations in the gene for MAP3K1 are also implicated in human developmental syndromes with similar symptoms as those driven by PPP2R3C mutations.
"Mutations that lead to a loss of function of PPP2R3C and mutations that lead to a gain of function of MAP3K1 give rise to similar symptoms," said Breslow. "And that makes sense as the proteins counteract each other. Both of those functional changes lead to the same imbalance."
The research also sheds new light on how mutations in PPP2RC3 and MAP3K1 can cause developmental syndromes.
When the researchers introduced one of the syndrome-related PPP2R3C mutations into cells, they found that the PPP2R3C protein didn't gather at centrosomes as it should, suggesting that the mutation compromised centrosome function. The new study is the first time that centrosome dysfunction has been linked to impaired gonadal development, which is one of the main symptoms of PPP2R3C- and MAP3K1-related syndromes.
"These findings may expand the scope of disease conditions that are related to centrosome dysfunction," said Breslow.
While centrosome dysfunction had previously been linked to cancer, the findings may also point to new targets for cancer treatment. Neuroblastomas and B cell leukemias often display strong dependence on PPP2R3C.
"Therefore, targeting PPP2R3C through drugs that inhibit its activity or that activate its opposing force - MAP3K1 - could be a potential therapeutic strategy," said Breslow.
