The binding of Mss4 to alpha-integrin subunits regulates matrix metalloproteinase activation and fibronectin remodeling.
In four independent yeast two-hybrid screens with the integrin alpha-subunits alpha3A, alpha6A, alpha7A, and alpha7B, we identified the Mss4 protein, a nucleotide exchange factor for exocytic Rab GTPases, as a novel integrin interacting protein. We have previously shown that it binds to the conserved KXGFFKR region of integrin alpha-subunits located directly beneath the cell membrane. Here we show that the binding site for integrins on Mss4 is overlapping with those for Rab GTPases. Functional analysis of the Mss4/integrin interaction revealed its importance for activation of matrix metalloproteinases (MMPs) and remodeling of secreted extracellular matrix (ECM) proteins. The exocytosis of all the proteins analyzed, however, was unaffected. Furthermore, our data suggest that Mss4 drives the coordinated action of the MT1-MMP/integrin protein complex, thus regulating the presence and activation of MT1-MMP at newly formed filopodia and lamellipodia. This in turn facilitates the conversion of pro-MMPs to MMPs, resulting in cleavage and remodeling of ECM proteins. C2C12 myoblasts with stably down-regulated Mss4 showed a disturbed fibronectin remodeling during differentiation, resulting in malfunctioned myotube formation.
Knoblauch
Alexander
A
Institute of Molecular Virology, Muenster University Hospital Medical School, Von-Esmarch-Str. 56, 48149 Muenster, Germany.
Will
Carola
C
Goncharenko
Grigori
G
Ludwig
Stephan
S
Wixler
Viktor
V
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D005353:Fibronectins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D020798:Two-Hybrid System Techniques
D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D039001:Integrin alpha Chains; D020782:Matrix Metalloproteinases