SC Connecticut News

Yale researchers have identified two proteins involved in centrosome function that could represent targets for treating congenital developmental disorders. The study, published in the journal Current Biology, focuses on the proteins PPP2R3C and MAP3K1.

David Breslow, senior author of the study and an assistant professor at Yale, explained that PPP2R3C was first identified during a genome-wide screen. "We were intrigued by this connection to disease," said Breslow. The research team found that mutations in the PPP2R3C gene are linked to developmental syndromes.

Breslow and his colleagues observed that PPP2R3C gathered at centrosomes of healthy cells, suggesting its role in centrosome function. However, knocking out its gene had varied effects: some cells died while others remained largely unaffected. "We were trying to figure out why there was so much variation," said Breslow. They discovered that the expression of a gene called MAP3K1 predicted this variability well.

Further analysis revealed that 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 cell death or major growth defects, but removing both proteins allowed cells to remain functional.

Mutations in MAP3K1 are also implicated in human developmental syndromes with symptoms similar to 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.

The study also links centrosome dysfunction to impaired gonadal development for the first time. Introducing syndrome-related PPP2R3C mutations into cells showed that the protein did not gather at centrosomes as it should, suggesting compromised centrosome function.

"These findings may expand the scope of disease conditions related to centrosome dysfunction," said Breslow. While previously linked to cancer, these findings might point to new targets for cancer treatment as well. Neuroblastomas and B cell leukemias often show strong dependence on PPP2R3C.

"Therefore, targeting PPP2R3C through drugs that inhibit its activity or activate its opposing force — MAP3K1 — could be a potential therapeutic strategy," said Breslow.