title: Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKCα and FAK/Fyn in promoting mesenchymal stem cell motility.
abstract: Netrin-1 (Ntn-1) is a potent inducer of neuronal cell migration; however, its molecular mechanism that guides the migratory behavior of stem cells has not been characterized. In this study, we investigate the role of Ntn-1 in promoting the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and its related signaling pathways. Ntn-1 (50 ng/mL) significantly increased motility of UCB-MSCs, which was inhibited by blocking antibodies for deleted in colorectal cancer (DCC) and integrin (IN) α6β4. Ntn-1 in DCC stimulated protein kinase Cα (PKCα) activation, but not PKCɛ, PKCθ, and PKCζ, while Ntn-1 in INα6β4 induced the phosphorylation of focal adhesion kinase (FAK) and Fyn. Notably, Ntn-1 induced phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and nuclear factor kappa-B (NF-κB), but they were concurrently downregulated by blocking the activities of PKCα, FAK, and Fyn. Ntn-1 uniquely increased the MMP-12 expression of all the matrix metalloproteinase (MMP) isoforms present in UCB-MSCs, though this was significantly blocked by an NF-κB inhibitor. Finally, Ntn-1 induced the MMP-12-dependent degradation of E-cadherin (E-cad), while Ntn-1 abrogated the interaction between E-cad and p120-catenin. In addition, Ntn-1 has the ability to stimulate cytoskeletal reorganization-related proteins, such as Cdc42, Rac1, Profilin-1, Cofilin-1, α-Actinin-4, and filamentous actin (F-actin) in UCB-MSCs. These results demonstrate that Ntn-1 induces MMP-12-dependent E-cad degradation via the distinct activation of PKCα and FAK/Fyn, which is necessary to govern the activation of ERK, JNK, and NF-κB in promoting motility of UCB-MSCs.
authors.affiliation: 1 Department of Veterinary Physiology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University , Seoul, Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Jung
authors.forename: Sang Yub
authors.initials: SY
authors.lastname: Oh
authors.forename: Min Sik
authors.initials: MS
authors.lastname: Yong
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D020013:Calcium Signaling; D002465:Cell Movement; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009414:Nerve Growth Factors / Q000502:physiology*; D000075388:Netrin-1; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D059748:Proteolysis; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C494957:FYN protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051076:Proto-Oncogene Proteins c-fyn; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12
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