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Multi-factorial modulation of IGD motogenic potential in MSF (migration stimulating factor)
Ian R Ellis1, Sarah J Jones, David Staunton
1Unit of Cell and Molecular Biology, The Dental School, College of Medicine, Dentistry and Nursing, University of Dundee, Park Place, DD1 4 HR, UK. irellis@dundee.ac.uk
Abstract:
Migration Stimulating Factor (MSF) is a genetically truncated isoform of fibronectin (Fn). MSF is a potent stimulator of fibroblast migration, whereas full length Fn is devoid of motogenic activity. MSF and Fn contain four IGD motifs, located in the 3rd, 5th, 7th and 9th type I modules; these modules are referred to as (3)FnI, (5)FnI, (7)FnI and (9)FnI, respectively. We have previously reported that mutation of IGD motifs in modules (7)FnI and (9)FnI of MSF is sufficient to completely abolish the motogenic response of target adult skin fibroblasts. We now report that the IGD sequences in (3)FnI and (5)FnI are also capable of exhibiting motogenic activity when present within fragments of MSF. When present within (1-5)FnI, these sequences require the presence of serum or vitronectin for their motogenic activity to be manifest, whereas the IGD sequences in (7)FnI and (9)FnI are bioactive in the absence of serum factors. All MSF and IGD-containing peptides stimulated the phosphorylation of the integrin binding protein focal adhesion kinase (FAK) but did not necessarily affect migration. These results suggest that steric hindrance determines the motogenic activity of MSF and Fn, and that both molecules contain cryptic bioactive fragments.
Insights
Migration Stimulating Factor (MSF), a fibronectin (Fn) isoform, stimulates fibroblast migration via specific IGD motifs. These motifs
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Fibronectin (Fn) is a key extracellular matrix protein involved in cell adhesion and migration.
- Migration Stimulating Factor (MSF) is a truncated Fn isoform with potent fibroblast motogenic activity, unlike full-length Fn.
- MSF and Fn contain four conserved Arginine-Glycine-Aspartic acid (RGD) motifs within their Type I modules (FnI).
Purpose of the Study:
- To investigate the role of IGD motifs in different FnI modules of MSF in stimulating fibroblast migration.
- To determine the influence of serum factors on the motogenic activity of MSF-derived peptides.
- To explore the relationship between focal adhesion kinase (FAK) phosphorylation and fibroblast migration induced by MSF and its fragments.
Main Methods:
- Site-directed mutagenesis of IGD motifs within MSF and Fn fragments.
- In vitro assays to measure fibroblast migration.
- Analysis of focal adhesion kinase (FAK) phosphorylation.
- Use of serum-depleted conditions and vitronectin supplementation.
Main Results:
- The IGD sequences in the (3)FnI and (5)FnI modules of MSF exhibit motogenic activity, particularly within the (1-5)FnI fragment.
- Motogenic activity of (3)FnI and (5)FnI IGD sequences requires serum or vitronectin, unlike the (7)FnI and (9)FnI IGD sequences.
- All tested MSF and IGD-containing peptides induced focal adhesion kinase (FAK) phosphorylation, but this did not always correlate with enhanced cell migration.
Conclusions:
- Steric hindrance plays a crucial role in determining the motogenic potential of MSF and Fn.
- Both MSF and full-length Fn harbor cryptic, bioactive fragments containing IGD motifs.
- The differential requirement for serum factors suggests distinct mechanisms of action for IGD motifs in different FnI modules.