By using a laser microbeam technology called optical tweezers, UC Irvine and UCLA researchers have uncovered fundamental properties of a key molecular signaling system involved with development, cancer and cardiovascular disease.
In collaboration, UCI’s Elliot Botvinick and UCLA’s Gerry Weinmaster published online in the journal Developmental Cell complementary studies in which they each used optical tweezers to detect and measure the mechanical force produced by cells when bound to Notch, a cellular pathway that ensures the correct cell types form at a precise time and location in the body.
“The Notch network is used repeatedly during the development of almost every cell type and must be tightly controlled, as inappropriate communication causes developmental defects and cancer,” said Weinmaster, a professor of biological chemistry and researcher at UCLA’s Jonsson Comprehensive Cancer Center. “Successful design and generation of Notch therapeutics demands a solid understanding of the basic mechanics of the Notch network.”
“Optical tweezers act as tiny tractor beams that can hold and manipulate microscopic beads coated with specific molecules,” said Botvinick, an assistant professor of biomedical engineering and surgery affiliated with the Beckman Laser Institute and The Edwards Lifesciences Center for Advanced Cardiovascular Technology at UCI. “When cells bind to and pull on the beads, researchers can measure cell-generated forces that are billions of times smaller than the weight of one teaspoon of sugar.”
Using this technology, the UCI-UCLA team found that communication via the Notch network involves a sort of tug-of-war between neighboring cells in which Notch molecules are unraveled by force to reveal hidden elements important for cell-to-cell communication.
Together with biochemical and biological cell analyses, their findings provide compelling evidence that pulling on Notch opens a network to deliver instructions for specific cellular responses.
The research sheds new light on the role of cells’ neighbors in the development and regulation of tissue and advances efforts to create new therapeutics.
Bhupinder Shergill of UCI and Laurence Meloty-Kapella, Abdiwahab Musse and Jane Kuon of UCLA contributed to the studies.
The National Institute of General Medical Sciences (grant number R01 GM085032), the National Center for Research Resources (P41 RR001192) and the National Institute of Biomedical Imaging & Bioengineering (P41 EB015890) — all of the National Institutes of Health — supported this work, as did the University of California Cancer Research Coordinating Committee, the Jonsson Cancer Center Foundation and the National Science Foundation (DMR 0805164).
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