Not your average PTPase: discovering PTEN’s substrate

July 17, 2017 § Leave a comment

Dixon&Maehama

In 1997, a couple of research groups discovered a gene now known as PTEN. The amino acid sequence of the protein it encoded resembled that of a protein tyrosine phosphatase, a similarity that implied PTEN might have a tumor-suppressing function. But the way the protein operated was not clear.

Jack E. Dixon, whose lab at the University of Michigan worked on protein tyrosine phosphatases, and his postdoc Tomohiko Maehama set out to determine PTEN’s substrate, which was integral to understanding how PTEN functioned. Other labs had been trying to determine what protein PTEN acted on, but with no luck. “It occurred to us, and this was I think one of the great insights, that maybe this protein tyrosine phosphatase isn’t really a protein phosphatase at all!” Dixon says. “Maybe it works on something else. And that turned out to be exactly correct.”

Dixon and Maehama discovered that in fact PTEN regulates the phosphorylation of a lipid, phosphatidylinositol 3,4,5-triphosphate (called PIP3 for short), a cell-growth-factor stimulant. PTEN was the first protein tyrosine phosphatase found to regulate a lipid instead of a protein.

The pair showed in a test tube that PTEN removes the phosphate from the 3 position on PIP3 to convert it to the nongrowth-stimulating PIP2. The resulting 1998 paper “was a particularly important one for shaping (scientists’) understanding of a key signaling pathway in normal cells,” says Eric Fearon, director of the University of Michigan Comprehensive Cancer Center. That pathway is the AKT signaling pathway, which is frequently disrupted in cancer.

Dixon and Maehama performed thin-layer chromatography and showed that PIP3 is downregulated as a result of transfecting in PTEN. “When we developed that TLC, down at the bottom of the gel, we could see PIP3 behave like we thought it would behave,” says Dixon. “That was a spectacular moment.”

By regulating PIP3, which is stimulated by insulin, PTEN serves as an important second messenger in cell signaling. “It’s like the brakes and the accelerator in a car,” Dixon says. “The accelerator is in this case insulin, and the brakes are PTEN. If you lose your brakes, you become tumorgenic.” PTEN downregulates PIP3 in cells without activating the growth enzyme phosphoinositide 3-kinase. PTEN is commonly found to be missing in cancers, including prostate and endometrial cancers; its absence is a common indicator that the tumor will grow quickly.

“Different scientific labs report different results, and when science is working well, one scientific publication is then the foundation for a subsequent one,” says Ramon Parsons, chairman of the department of oncological sciences at the Icahn School of Medicine at Mt. Sinai, who led one of the groups that discovered PTEN. Within six months, he says, a whole range of groups were able to confirm and build upon Dixon and Maehama’s findings.

Since whole-exome sequencing became possible in the past decade, Parsons says, it has become clear that PTEN is likely the most frequently mutated tumor suppressor besides P53 in all cancers.

Dixon and Maehama’s JBC paper is “certainly viewed as one of the seminal papers in the whole study of PTEN as a tumor-suppressor gene,” Fearon says.

It is now known that PTEN plays an important role outside of cancer in processes such as brain development. In fact, PTEN mutations have been tied to a subset of autism resulting from the uncontrolled growth of nerve fibers in the brain.

Dixon and Maehama’s 1998 paper “was the first paper to definitively establish the function of PTEN as a tumor-suppressor gene in cell signaling,” a critical step in exploring therapeutic effects in cancers, Fearon says. Small molecules are being studied to target defects in the AKT pathway.

“Even though it was a very short paper, I think it was the pivotal paper in highlighting the function of PTEN,” Fearon says. “It’s beautiful work, and extremely well done, which is why I think it’s stood the test of time.”

This post was written by Alexandra Taylor (alexandraataylor[at]gmail.com), a master’s candidate in science and medical writing at Johns Hopkins University. She writes about “Classic” articles in the Journal of Biological Chemistry. See more of her work in JBC here.

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