Metalloprotease‐induced ectodomain shedding of neural cell adhesion molecule (NCAM)

Hinkle, C. Leann; Diestel, Simone; Lieberman, Jeffrey A.; Maness, Patricia F.

doi:10.1002/neu.20257

Cited by 100 publications

(91 citation statements)

References 108 publications

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“…In this scenario, the concurrent effects of soluble NCAM and cell contact-dependent interactions after polySia removal would predict that loss of polySia increases cell surface NCAM by inhibition of shedding. There is, however, no reason to assume that NCAM shedding is facilitated by the presence of polySia and all data so far indicate that shed NCAM fragments are not polysialylated (Diestel et al, 2005;Hübschmann et al, 2005;Hinkle et al, 2006;Kalus et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Polysialic acid controls NCAM signals at cell–cell contacts to regulate focal adhesion independent from FGF receptor activity

Eggers

Werneburg

Schertzinger

et al. 2011

Journal of Cell Science

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SummaryThe polysialic acid (polySia) modification of the neural cell adhesion molecule NCAM is a key regulator of cell migration. Yet its role in NCAM-dependent or NCAM-independent modulation of motility and cell-matrix adhesion is largely unresolved. Here, we demonstrate that loss of polySia attenuates tumour cell migration and augments the number of focal adhesions in a cell-cell contact-and NCAM-dependent manner. In the presence or absence of polySia, NCAM never colocalised with focal adhesions but was enriched at cell-cell contacts. Focal adhesion of polySia-and NCAM-negative cells was enhanced by incubation with soluble NCAM or by removing polySia from heterotypic contacts with polySia-NCAM-positive cells. Focal adhesion was compromised by the src-family kinase inhibitor PP2, whereas loss of polySia or exposure to NCAM promoted the association of p59Fyn with the focal adhesion scaffolding protein paxillin. Unlike other NCAM responses, NCAM-induced focal adhesion was not prevented by inhibiting FGF receptor activity and could be evoked by NCAM fragments comprising immunoglobulin domains three and four but not by the NCAM fibronectin domains alone or by an NCAM-derived peptide known to interact with and activate FGF receptors. Together, these data indicate that polySia regulates cell motility through NCAM-induced but FGF-receptor-independent signalling to focal adhesions.

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Section: Discussionmentioning

confidence: 99%

Polysialic acid controls NCAM signals at cell–cell contacts to regulate focal adhesion independent from FGF receptor activity

Eggers

Werneburg

Schertzinger

et al. 2011

Journal of Cell Science

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“…Previous studies have demonstrated that several metalloproteases, such as MMP-2 and MMP-9, as well as the ADAM family of metalloproteases, target NCAM (Brennaman et al, 2014;Hinkle et al, 2006;Hübschmann et al, 2005;Shichi et al, 2011). It has also been shown that inhibition of MMP-2 and MMP-9 prevents NCAM shedding, indicating the roles of these MMPs in NCAM cleavage (Hübschmann et al, 2005;Shichi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it seemed unlikely that PREP itself is able to degrade NCAM. It has been demonstrated previously that NCAM molecule degradation might be mediated by the matrix metalloproteases (MMPs) (Brennaman et al, 2014;Hinkle et al, 2006;Hübschmann et al, 2005;Shichi et al, 2011). Therefore, to test whether increased expression and activity of PREP might be involved in the activation of MMPs, we measured the expression levels and activity of MMP-9.…”

Section: Impaired Differentiation Of Prep-overexpressing Cellsmentioning

confidence: 99%

“…It has been demonstrated that NCAM can be cleaved extracellularly by metalloproteinases and other proteolytic enzymes (Brennaman et al, 2014;Hinkle et al, 2006;Hübschmann et al, 2005;Kalus et al, 2006). Moreover, metalloproteinase-dependent shedding of NCAM induces release of soluble forms of NCAM consisting of several polypeptides with molecular weights ranging from 80 kDa to 200 kDa (Krog et al, 1992;Nybroe et al, 1989;Sadoul et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

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Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Jaako

Waniek

Parik

et al. 2016

Journal of Cell Science

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Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newlydiscovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM.

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“…in vitro studies have shown that ADAM8 can process several molecules including CD40, tumor necrosis factor-a, IL1R and the immunoglobulin E receptor CD23 (Fourie et al, 2003). Only the CHL1 neural-cell adhesion homolog (Naus et al, 2004), NCAM-140 (Hinkle et al, 2006) and L-selectin (Gomez-Gaviro et al, 2007) have been shown to be processed by ADAM8 in vivo. Whether these or other unknown adhesion molecules can be targeted by ADAM8 during invasion remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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ADAMs (a disintegrin and metalloprotease) are transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. However, its contribution to tumorigenesis in the context of lung cancer metastasis remains unknown. Native ADAM8 expression levels were lower in lung cancer cell lines. In contrast, we identified and characterized two novel spliced isoforms encoding truncated proteins, D18a and D14 0 , which were present in several tumor cell lines and not in normal cells. Overexpression of D18a protein resulted in enhanced invasive activity in vitro. ADAM8 and its D14 0 isoform expression levels were markedly increased in lung cancer cells, in conditions mimicking tumor microenvironment. Moreover, addition of supernatants from D14 0 -overexpressing cells resulted in a significant increase in tartrate-resistant acid phosphatase þ cells in osteoclast cultures in vitro. These findings were associated with increased pro-osteoclastogenic cytokines interleukin (IL)-8 and IL-6 protein levels. Furthermore, lung cancer cells overexpressing D14 0 increased prometastatic activity with a high tumor burden and increased osteolysis in a murine model of bone metastasis. Thus, the expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.

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Metalloprotease‐induced ectodomain shedding of neural cell adhesion molecule (NCAM)

Cited by 100 publications

References 108 publications

Polysialic acid controls NCAM signals at cell–cell contacts to regulate focal adhesion independent from FGF receptor activity

Polysialic acid controls NCAM signals at cell–cell contacts to regulate focal adhesion independent from FGF receptor activity

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

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