PRL1 promotes cell migration and invasion by increasing MMP2 and MMP9 expression through Src and ERK1/2 pathways.
The PRL (phosphatase of regenerating liver) phosphatases represent a distinct class of protein tyrosine phosphatases, which are implicated in tumorigenesis and metastasis processes. Accumulating evidence indicates that alteration of PRL1 expression affects cell motility and tumor metastasis, although the biochemical pathways regulated by PRL1 remain less well defined. We find that elevated expression of PRL1 increases the levels of the matrix metalloproteinases MMP2 and MMP9. We have studied whether MMP2 and MMP9 are regulated by PRL1 and participate in PRL1-dependent cell migration and invasion. To this end, knockdown or inhibition of MMP2 and MMP9 by either siRNA or a specific small molecule inhibitor blocks PRL1-mediated cell migration and invasion. In addition, we report that upregulation of PRL1 activates the Src kinase through increased Tyr416 phosphorylation, which culminates in the phosphorylation of focal adhesion proteins FAK and p130(Cas), as well as ERK1/2 activation. We provide evidence that both the Src and ERK1/2 pathways contribute to the increased motility of the PRL1 cells. We further demonstrate that Src and ERK1/2 activities are required for the PRL1-induced increase in the levels of MMP2 and MMP9, likely through activation of transcription factors AP1 and Sp1. Accordingly, increased PRL1 expression results in activation of Src and ERK1/2, which stimulates MMP2 and MMP9 production, leading to increased cell migration and invasion.
Luo
Yong
Y
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
Liang
Fubo
F
Zhang
Zhong-Yin
ZY
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C490198:PTP4A1 protein, human; D017027:Protein Tyrosine Phosphatases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9