TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling

Lee, Soo-Youn; Kim, Jung Mi; Cho, Soo Young; Kim, Hyun Suk; Shin, Hee Sun; Jeon, Jeong Yong; Kausar, Rukhsana; Jeong, Sun Young; Lee, Young Seek; Lee, Myung Ae

doi:10.1042/bj20131119

Cited by 47 publications

(37 citation statements)

References 59 publications

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“…Timp1 protein product is a metalloproteinase inhibitor known to be involved in cell adhesion and migration of human neural stem cells (hNSCs). In fact, through its cell surface receptor CD63, TIMP-1 activates β1 integrin, FAK (focal adhesion kinase) and the PI3K (phosphoinositide 3-kinase) signal transduction pathway, resulting in the migration of hNSCs (Lee et al, 2014). Due to its chemoattractant properties, TIMP-1 has been identified in the same study as a therapeutic target for human glioma.…”

Section: Resultsmentioning

confidence: 99%

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Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile¹,

Ceccarelli²,

Micheli³

et al. 2016

Front. Pharmacol.

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We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/−/Tis21KO). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+/−/Tis21 wild-type vs. Ptch1+/−/Tis21 knockout), among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

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Section: Resultsmentioning

confidence: 99%

“…Its signal trasduction pathway results in the migration of hNSCs, showing chemoattractant properties and being identified in the same study as a therapeutic target for human glioma (Lee et al, 2014). Here we suggest the same prospective use of Timp1 in MB Shh-type.…”

Section: Resultsmentioning

confidence: 99%

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile¹,

Ceccarelli²,

Micheli³

et al. 2016

Front. Pharmacol.

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“…MMP-independent pathways can occur through TIMP-1 interaction with the cell surface tetraspanin CD63/integrin complex, which initiates PI3K/Akt-dependent pro-survival signaling [163, 291-293]. Interestingly, immunoprecipitation studies have demonstrated that mutated TIMP1, which lacks MMP inhibitory function, binds CD63 to a higher degree when compared to wild type protein [294].…”

Section: Rns-derived Signaling In Cancermentioning

confidence: 99%

Signaling and stress: The redox landscape in NOS2 biology

Thomas

Heinecke

Ridnour

et al. 2015

Free Radical Biology and Medicine

122

109

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Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including the chemistry of RNS and their molecular targets.

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“…TNF-α promotes survival of human quiescent bone marrow-derived CD34 + Burst Forming Unit-Erythrocyte (BFU-E) and facilitates the clonal expansion of JAK2 V617F -positive cells in MPNs [26, 32]. TIMP-1, through receptor (CD63) binding, promotes cell survival, differentiation and migration; also, TIMP-1 displays cytokine-like features in the HSPC compartment [33–35]. It was initially found to enhance the proliferation of erythroid cells [36]; also, we recently demonstrated that TIMP-1 increases the clonogenic efficiency of normal CB-derived progenitor cells [37].…”

Section: Introductionmentioning

confidence: 99%

Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study

et al. 2016

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Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.

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TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling

Cited by 47 publications

References 59 publications

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Signaling and stress: The redox landscape in NOS2 biology

Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study

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