Membrane-type 1 matrix metalloproteinase regulates cell migration during zebrafish gastrulation: evidence for an interaction with non-canonical Wnt signaling.
Key to invasiveness is the ability of tumor cells to modify the extracellular matrix, become motile, and engage in directed migration towards the vasculature. One significant protein associated with metastatic progression is membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14). How MMP14 activity is coordinated with other signaling pathways to regulate cell migration in vivo is largely unknown. Here we have used zebrafish embryogenesis as a model to understand the potential relationship between MMP14-dependent pericellular proteolysis, cell polarity, and motility. Knockdown of zebrafish Mmp14 function disrupted gastrulation convergence and extension cell movements and craniofacial morphogenesis. Using time-lapse imaging and morphometric analyses, we show that Mmp14 is required for proper cell polarity underlying the directed migration of mesodermal cells during gastrulation. We have identified a genetic interaction between mmp14 and non-canonical Wnt signaling, a pathway that also regulates cell polarity in embryonic tissues and is increasingly being linked with tumor cell migration. Finally, we demonstrate that Van Gogh-like 2, a key regulator of the non-canonical Wnt pathway, co-localizes with MMP14 and becomes redistributed towards the leading edge of polarized human cancer cells. Together, our results support the notion that pathways regulating pericellular proteolysis and cell polarity converge to promote efficient cell migration.
Coyle
Rebecca C
RC
Department of Medicine/Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Latimer
Andrew
A
Jessen
Jason R
JR
D000818:Animals; D019521:Body Patterning; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity; D003599:Cytoskeleton / Q000378:metabolism; D054262:Gastrulation; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C468513:VANGL2 protein, human; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D053511:Matrix Metalloproteinase 14