A novel role for IQGAP1 protein in cell motility through cell retraction

Abstract

IQGAP1 has emerged as a key component in the regulation of cytoskeleton dynamics during cell migration, maintenance of adherens junctions, microbial pathogenesis and intracellular trafficking. IQGAP1 is known to localize to the protruding edge of lamellipodia in a variety of cell types and interact with regulators of actin dynamics. Here, we provide evidence suggesting a novel role of IQGAP1 in cell motility through cell edge retraction. In some of the cell lines examined, IQGAP1 was markedly separated from WAVE localization suggesting IQGAP1 may localize to retracting edges. B16F10 mouse melanoma cells exhibited the most restricted separation in which the appearance of GFP-IQGAP1 correlated with cell edge retraction velocity and the disappearance of mCherry-Arp3. These results demonstrate that in some cell types IQGAP1 may function to promote cell retraction not lamellipodium edge protrusion. In addition, we examined co-localization of IQGAP1 with adhesion site markers, myosin IIA, calmodulin and IQGAP2. In areas rich in IQGAP1 there was decreased immunofluorescence staining of vinculin, paxillin and phosphorylated-tyrosine indicating adhesion site disassembly. Interestingly, calmodulin, but not myosin IIA or IQGAP2, co-localized with IQGAP1 in areas of cell retraction. Overall these results suggest a new role of IQGAP1, distinct form IQGAP2, in cell migration through up regulation of contractility and downregulation of adhesion sites potentially through calmodulin interaction.

A resilient formin-derived cortical actin meshwork in the rear drives actomyosin-based motility in 2D confinement

“…Although vertebrates do not express Ctx, we propose that human IQGAP1 might already substitute its function. Consistent with previous work 45 58 , we show that IQGAP1 accumulates in the trailing edge of B16-F1 cells ( Fig. 9a ).…”

“…Since actomyosin-based contraction is exploited by many cell types to drive or support motility, we finally asked whether higher eukaryotes could employ a related mechanism to generate a rigid cortex in the rear. Although vertebrates do not express Ctx, human IQGAP1 by itself might replace its function, since it was previously reported to crosslink actin filaments in vitro 43 , and have shown to accumulate in the trailing edge, at least in B16-F10 and WM239A melanoma cells 44 45 . To corroborate these findings in a commonly used and highly migratory cell line, we transfected B16-F1 mouse melanoma cells with enhanced (E)GFP-tagged IQGAP1 (ref.…”

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…Different IQGAP isoforms interact differentially with a variety of target proteins implicated in tumor cell invasiveness and metastatic capacity (reviewed in [296]). In fact, IQGAP1, but not IQGAP2, also participated in the retraction of lamellipodia, decreasing the number of adhesion points most likely upon CaM interaction [297]. Non-invasive MCF-7 human breast adenocarcinoma cells expressing mutated IQGAP1 affecting the Ca 2+ /CaM-binding but not apo-CaM binding sites increased the rate of cell migration [298].…”

IQGAPs choreograph cellular signaling from the membrane to the nucleus

“…Roles for IQGAP1 at the trailing edge are now being defined. In some cell lines, such as B16F10 mouse melanoma, IQGAP1 is present in regions of the cell undergoing retraction, distinct from the leading edge or focal adhesions [29]. By contrast, IQGAP2 localizes to protruding edges [29], suggesting distinct roles for the isoforms in cell motility.…”

“…In some cell lines, such as B16F10 mouse melanoma, IQGAP1 is present in regions of the cell undergoing retraction, distinct from the leading edge or focal adhesions [29]. By contrast, IQGAP2 localizes to protruding edges [29], suggesting distinct roles for the isoforms in cell motility. The secreted signaling protein Wnt5a promotes the formation of the Wnt-receptor-actin-myosin-polarity (WRAMP) structure, which coordinates retraction at the trailing edge.…”