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)P ₂ at the membrane and thereby limiting recruitment of lamellipodin [a PI(3,4)P 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.

Expression of several actin-binding proteins including profilin-1 is up-regulated during capillary morphogenesis of endothelial cells, the biological significance of which remains unknown. Specifically, we hypothesized that profilin-1 is important for endothelial migration and proliferation. In this study, we suppressed profilin-1 expression in human umbilical vein endothelial cells by RNA-interference. Gene silencing of profilin-1 led to significant reduction in the formation of actin filaments and focal adhesions. Loss of profilin-1 expression was also associated with reduced dynamics of cell-cell adhesion. Data from both wound-healing experiments and time-lapse imaging of individual cells showed inhibition of cell migration when profilin-1 expression was suppressed. Cells lacking profilin-1 exhibited defects in membrane protrusion, both in terms of its magnitude and directional persistence. Furthermore, loss of profilin-1 expression inhibited cell growth without compromising cell survival, at least in the short-term, thus suggesting that profilin-1 also plays an important role in endothelial proliferation as hypothesized. Finally, silencing profilin-1 expression suppressed matrigel-induced early cord morphogenesis of endothelial cells. Taken together, our data suggest that profilin-1 may play important role in biological events that involve endothelial proliferation, migration and morphogenesis.

Actin-based cell migration is a fundamental cellular activity that plays a crucial role in a wide range of physiological and pathological processes. An essential feature of the remodeling of actin cytoskeleton during cell motility is the de novo synthesis of factors involved in the regulation of the actin cytoskeleton and cell adhesion in response to growth-factor signaling, and this aspect of cell migration is critically regulated by serum-response factor (SRF)-mediated gene transcription. Myocardin-related transcription factors (MRTFs) are key coactivators of SRF that link actin dynamics to SRF-mediated gene transcription. In this Review, we provide a comprehensive overview of the role of MRTF in both normal and cancer cell migration by discussing its canonical SRF-dependent as well as its recently emerged SRF-independent functions, exerted through its SAP domain, in the context of cell migration. We conclude by highlighting outstanding questions for future research in this field.

Expression of profilin-1 (Pfn1) is downregulated in breast cancer cells, the functional significance of which is yet to be understood. To address this question, in this study we evaluated how perturbing Pfn1 affects motility and invasion of breast cancer cells. We show that loss of Pfn1 expression leads to enhanced motility and matrigel invasiveness of MDA-MB-231 breast cancer cells. Interestingly, silencing Pfn1 expression is associated with downregulation of both cell–cell and cell–matrix adhesions with concomitant increase in motility and dramatic scattering of normal human mammary epithelial cells. Thus, these data for the first time suggest that loss of Pfn1 expression may have significance in breast cancer progression. Consistent with these findings, even a moderate overexpression of Pfn1 induces actin stress-fibres, upregulates focal adhesion, and dramatically inhibits motility and matrigel invasiveness of MDA-MB-231 cells. Using mutants of Pfn1 that are defective in binding to either actin or proline-rich ligands, we further show that overexpressed Pfn1 must have a functional actin-binding site to suppress cell motility. Finally, animal experiments reveal that overexpression of Pfn1 suppresses orthotopic tumorigenicity and micro-metastasis of MDA-MB-231 cells in nude mice. These data imply that perturbing Pfn1 could be a good molecular strategy to limit the aggressiveness of breast cancer cells.

Profilin-1 (Pfn1) is a ubiquitously expressed actin-monomer binding protein that has been linked to many cellular activities ranging from control of actin polymerization to gene transcription. Traditionally, Pfn1 has been considered to be an essential control element for actin polymerization and cell migration. Seemingly contrasting this view, a few recent studies have shown evidence of an inhibitory action of Pfn1 on motility of certain types of carcinoma cells. In this review, we summarize biochemistry and functional aspects of Pfn1 in normal cells and bring in newly emerged action of Pfn1 in cancer cells that may explain its context-specific role in cell migration.