Profilin1 regulates PI(3,4)P-2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells

• Main Authors: Bae, Yong Ho (Author), Ding, Zhijie (Author), Das, Tuhin (Author), Wells, Alan (Author), Gertler, Frank (Contributor), Roy, Partha (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: National Academy of Sciences (U.S.), 2011-07-22T17:03:08Z.
• Subjects: Article
• Online Access: Get fulltext

Profilin1, a ubiquitously expressed actin-binding protein, plays a critical role in cell migration through actin cytoskeletal regulation. Given the traditional view of profilin1 as a promigratory molecule, it is difficult to reconcile observations that profilin1 is down-regulated in various invasive adenocarcinomas and that reduced profilin1 expression actually confers increased motility to certain adenocarcinoma cells. In this study, we show that profilin1 negatively regulates lamellipodin targeting to the leading edge in MDA-MB-231 breast cancer cells and normal cells; profilin1 depletion increases lamellipodin concentration at the lamellipodial tip (where it binds Ena/VASP), and this mediates the hypermotility. We report that the molecular mechanism underlying profilin1's modulation of lamellipodin localization relates to phosphoinositide control. Specifically, we show that phosphoinositide binding of profilin1 inhibits the motility of MDA-MB-231 cells by negatively regulating PI(3,4)P2 [PI(3,4)P subscript 2]at the membrane and thereby limiting recruitment of lamellipodin [a PI(3,4)P2-binding [PI(3,4)P subscript 2 - binding] protein] and Ena/VASP to the leading edge. In summary, this study uncovers a unique biological consequence of profilin1-phosphoinositide interaction, thus providing direct evidence of profilin1's regulation of cell migration independent of its actin-related activity.
National Institutes of Health (U.S.) (Grant CA108607)
National Institutes of Health (U.S.) (Grant GM58801)