title: MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility.
abstract: Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP. We identified the tumor suppressor gene SPRY4 as a new transcriptional target of MT1-MMP that is negatively regulated by the protease. Knockdown of MT1-MMP enhances SPRY4 expression at the mRNA and protein level. SPRY4 expression inversely correlates with that of MT1-MMP in melanoma samples and importantly, correlates with melanoma patient survival. SPRY4 modulates MT1-MMP dependent cell migration such that inhibition of SPRY4 rescues cell migration that has been impaired by MT1-MMP knock down. MT1-MMP decreases SPRY4 in part through an MMP2/RAC1 axis we previously show promotes cell motility downstream of MT1-MMP. These results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility.
authors.affiliation: From the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Khvaramze
authors.initials: K
authors.lastname: Shaverdashvili
authors.affiliation: From the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Keman
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Departments of Dermatology, Urology and Medicine, New York University Langone Medical Center, New York, NY, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: From the Department of Pathology and Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Kord
authors.initials: K
authors.lastname: Honda
authors.affiliation: From the Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Rauli
authors.initials: R
authors.lastname: Jobava
authors.affiliation: From the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C499038:SPRY4 protein, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: SPRY4; cell migration; matrix metalloproteinase (MMP); melanoma