Universal gene signaling mechanism identified by UB molecular researchers

Aug 14 2008

A novel gene signaling mechanism that controls whether a stem cell develops into its destined tissue or fails to differentiate and becomes cancer has been identified by researchers in the multi-laboratory Molecular and Structural Neurobiology and Gene Therapy Program based at the University at Buffalo.

The new pathway, identified as Integrative FGFR1 Signaling (INFS), presents a new and promising target for in vivo neural stem cell therapies and anticancer strategies.

Michal K. Stachowiak, Ph.D., UB associate professor of pathology and anatomical sciences and head of the research program that identified this new signaling system, describes it as a universal "feed-forward-and-gate" signaling process. Its discovery puts to rest the idea that cell differentiation occurs out of a disorganized chaos of signals.

In simple terms, "feed-forward-and-gate" involves two pathways working in tandem. One pathway "feeds forward" the classical cascade of signals initiated by diverse membrane receptors that activate sequence-specific transcription factors. In parallel, a separate pathway "counts" the signals and determines if enough "pros" versus "cons" have been received to open the gate and allow a coordinated signal to execute multi-gene developmental programs.

This mechanism involves an unexpected behavior of a known protein called Fibroblast Growth Factor Receptor-1 (FGFR1) which, instead of attaching to the cell surface, is transported to the nucleus as the universal feed-forward signal. Stachowiak and his wife Ewa Stachowiak, Ph.D., an instructor in pathology and anatomical sciences, have been working on the project for more than a decade.

"I have been intrigued for years by the question of how a cell knows what to do," said Stachowiak. "It is exposed to a plethora of signals and many stimuli, and somehow it moves forward in the right direction most of the time. If it doesn't know what to do, the cell may continue to divide and become a cancer.

"Nature doesn't like chaos, so there had to be something logical, some process that tells the cell what to become, a pathway that integrates a variety of stimuli and comes up with a 'conclusion,'" he said. "INFS does that. It tells the cell 'Don't start anything until I tell you.' It also is called a safety mechanism. It's a bean counter -- it counts the signals and 'averages' them until there is enough to open the gate."

Until recently, explained Stachowiak, researchers were preoccupied with details of the individual classical signaling cascades, neglecting the fundamental question of how these signals can be integrated to command the multi-gene developmental programs. They were not interested in Stachowiak's findings.

Meanwhile, young scientists at other institutions were contacting him to report they were arriving at similar conclusions, but were hesitant to go public and face the same criticism. Stachowiak and these researchers joined forces in 2005 and organized a session on their new theory of cell signaling at the American Society of Cell Biology meeting in San Francisco.

"Scientists at the meeting finally accepted this new pathway," Stachowiak. "We were the first to have the guts to talk about it publicly. It took courage, and sticking to an important scientific principal -- to report on nature as it is, rather than what was thought to be the situation -- when our theory challenged the established scientific opinion. This unconventional, anti-doctrinaire approach has allowed us to explore areas and ideas that were overlooked by many scientists."

Stachowiak and his UB group published several papers as the research progressed. The most recent publication, a review of the research to date titled "Integrative nuclear signaling in cell development -- a role for FGF Receptor-1" appeared in the November 2007 issue of DNA and Cell Biology.

The scientific community has shown great interest in the "feed-forward-and-gate" signaling process, which Stachowiak has discussed in several invited lectures, most recently at the University of Hannover, Germany, this June. Another paper is due to be published in the near future.

"The INFS pathway offers a novel target for in vivo neural stem cell therapies and anticancer strategies," Stachowiak said. "It is a universal mechanism that can apply to many areas of biology. We have a key. Now we can move on to develop therapies."

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. The School of Medicine and Biomedical Sciences is one of the five schools comprising UB's Academic Health Center. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.