研究人员发现调控细胞蛋白质稳定性的生物机制

The cell signaling pathway known as Wnt, commonly activated² in cancers, causes internal membranes³（内膜） within a healthy cell to imprison⁵（监禁，关押） an enzyme⁶ that is vital in degrading proteins, preventing the enzyme from doing its job and affecting the stability of many proteins within the cell, researchers at UCLA's Jonsson Comprehensive Cancer Center have found. The finding is important because sequestering⁷（使隔绝，使隐退） the enzyme, Glycogen Synthase Kinase 3 (GSK3), results in the stabilization⁸ of proteins in the cell, at least one of which is known to be a key player in cancer, said Dr. Edward De Robertis, senior author of the study and a Jonsson Cancer Center scientist.

"Surprisingly, we found that the degradation⁹ of about 20 percent of proteins in the cell is triggered by the GSK3 enzyme," said De Robertis, who also is a Howard Hughes Medical Institute investigator¹⁰. "That's a great many proteins and one of them, beta-Catenin, is known to cause cancer. We also know that Wnt signaling is activated in about 85 percent of colorectal cancers（结肠直肠癌） and other forms of cancer start with mutations that activate¹ Wnt signaling. So, this finding could have ramifications¹¹（分枝，分叉） for potential new treatments for cancer."

The study, a collaboration¹² with cell biologist Dr. David D. Sabatini of New York University, appears in the Dec. 23, 2010 issue of the peer-reviewed journal Cell.

De Robertis said Wnt signaling requires inhibition of GSK3, but the enzyme sequestration（隔离，扣押） mechanism¹³ was not known until now. The enzyme becomes imprisoned¹⁴ inside membrane⁴-bounded organelles（细胞器） , known as multivesicular bodies, found within the cell cytoplasm.

"We knew these multivesicular bodies were involved in degradation of proteins, but that they had a role in how cells communicate with each other by switching on a signaling pathway was not known," De Robertis said. "This finding raises the possibility that other signaling pathways could operate through this sequestration mechanism."

When cells receive Wnt, it's a signal for cells to degrade their proteins more slowly, to keep them for a longer period of time because they're needed to regulate cell functions, such as proliferation. Wnt signaling, for example, is very high in all stem cells and rises during the regeneration of most tissues, De Robertis said.

"Perhaps one of the functions of Wnt is to stabilize¹⁵ certain cell functions and it may be that cancer needs higher protein stability than other cells, which is why increased Wnt signaling if found in so many cancers," De Robertis said. "These findings may give us new therapeutic¹⁶ targets for preventing sequestrations inside these membranes, which would decrease Wnt signaling."

De Robertis said this study also links two formerly¹⁷ unrelated areas of biology. The cell cytoplasm（细胞质） is filled with internal membranes that shuttle proteins to their final destinations. Cells in tissues communicate with their neighbors by receiving external signals called growth factors. The new work links the cell biology of membrane trafficking and the interpretation¹⁸ of the signals that control cell proliferation.

"Protein degradation is a very important part of the life of a cell. About 10 percent of the genes¹⁹ in the genome are dedicated²⁰ to protein degradation," De Robertis said. "We now know that Wnt causes an enzyme that degrades proteins to be sequestered²¹ and because of that becomes a regulator of cellular²² protein stability."

De Robertis characterized this finding as "very unexpected."

"No one thought you could have cell signaling through sequestration of an enzyme inside a membrane organelle like these multivesicular bodies," he said. This is because the GSK3 enzyme is normally found everywhere in the cell, but becomes tightly bound to the internal side of membrane receptors when the Wnt signal is received.