Skp1/Cull/F-box protein complexes is a name only a molecular biologist could love, and even Michele Pagano calls them "SCFs" for short. F-box proteins are subunits of the SCF ubiquitin ligase family of enzymes and are almost ubiquitous in the cell's workings, seemingly everywhere and doing everything.
When Pagano first began identifying human F-box proteins in 1999, he found 26 of them, a number that subsequently grew to 69. Nine years later, scientists have managed to pin down the function or targets for about a dozen of the 69 F-box proteins identified. The rest have remained "orphans," that is, they have no known protein targets or function ascribed to them. Yet, having worked out the cellular functions of only a small number of F-box proteins, Pagano concludes that while the majority of the F-box proteins may be orphans, they have powerful connections.
Pagano was born, raised, and educated in Naples (in the southern part of Italy), which for centuries was the capital of its own country and still is in Pagano's heart. Northern Italy, he says jokingly, reminds him of Germany, where he lived and worked at the European Molecular Biology Laboratory (EMBL) in Heidelberg. In 1990, Pagano left Naples after receiving his M.D. and research degree from the Federico II University (which, founded in 1224, is the oldest school of medicine in the Western world) to pursue a basic research career in Heidelberg. After only two years, he moved to Boston to join a biotech start-up, cofounded and run by his former boss at EMBL. To pursue his long-term professional career goals, in late 1996 Pagano shifted back to academic science at the New York University School of Medicine.
His original decision to become a scientist tugged at his parents' hearts, Pagano recalls. His mother, a criminal lawyer, and his father—an extremely busy cardiologist in Naples—couldn't understand why their son would turn his back on clinical medicine. "My parents worried that I would not make a living as a scientist," Pagano recalls. "Only after I moved from Germany to the United States and then here to NYU did my parents think that maybe I would not die of starvation and be found frozen under a bridge."
Since he joined NYU, Pagano has been working on the ubiquitin system, which is part of the cell's recycling organization. Ubiquitin is attached as a "tag" to proteins that have completed their cellular tasks or are worn out, misfolded, or in surplus. Once proteins are tagged by ubiquitin, they are degraded back into amino acids by cellular grinders called proteasomes. F-box proteins make sure that ubiquitin tags are stuck onto the right "molecular waste." Thus, their job takes F-box proteins everywhere and brings them on the scene during the cell's most delicate operations. That's what would be expected from the cell's waste management system.
Not everyone expected this family of orphans to wield power over so many important cellular processes. Pagano's research group has revealed that F-box proteins help control cell proliferation, DNA-damage checkpoints, chromosomal stability, ribosomal biogenesis, protein synthesis, apoptosis, neurogenesis, and even the setting of the circadian clock. Orphans, after all, must fend for themselves.
Pagano has also found that many F-box proteins have connections to cancer. They play key roles in both tumor suppression and tumor activation. He discovered that low levels of certain F-box proteins were by themselves a warning that a tumor may be developing. In other cases, such as in breast cancer, Pagano demonstrated that high levels of one particular F-box protein represent a diagnostic sign that the cancer is of a highly aggressive form. Raising levels of a different F-box protein seems instead to sensitize tumors to anticancer drugs.
As an HHMI investigator, Pagano will conduct his research from his longtime academic home at New York University School of Medicine, in his adopted favorite city on earth. "I've become a New Yorker and begun speaking New Yorkese," Pagano proudly declares, ironically pronouncing it in the Italian-American way as "New Yor-kay-zee." Pagano intends to use his new position to refine the diagnostic signatures of F-box proteins and give more of these orphans a home in the scientific world.