Membrane-type 1 matrix metalloproteinase stimulates cell migration through epidermal growth factor receptor transactivation.
Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP-dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP-induced EGFR transactivation also involves G(i) protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP-dependent processes associated with tumor cell invasion and angiogenesis.
Langlois
Stéphanie
S
Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal, Centre de Cancérologie Charles-Bruneau, 3175 Chemin Côte-Ste-Catherine, Montreal, Quebec, Canada H3T 1C5.
Nyalendo
Carine
C
Di Tomasso
Geneviève
G
Labrecque
Lyne
L
Roghi
Christian
C
Murphy
Gillian
G
Gingras
Denis
D
Béliveau
Richard
R
D000818:Animals; D019556:COS Cells; D002417:Cattle; D002454:Cell Differentiation; D002465:Cell Movement; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015533:Transcriptional Activation
D008246:Lysophospholipids; D049452:Green Fluorescent Proteins; C060506:sphingosine 1-phosphate; D066246:ErbB Receptors; D053511:Matrix Metalloproteinase 14; D013110:Sphingosine