ADAMs and ADAMTSs in cancer

Turner, Sharon L; Blair-Zajdel, Maria E; Bunning, R.A.D.

doi:10.1080/09674845.2009.11730257

Cited by 34 publications

(25 citation statements)

References 95 publications

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“…Inappropriate synthesis of growth factors by cells expressing the appropriate receptor can generate an autocrine loop driving signaling. This can also be achieved through cleavage and release of anchored soluble growth factors by surface ADAM proteases, which are activated downstream from oncogenic signaling pathways (Turner et al 2009). Alternatively, the growth factor may be synthesized by a neighboring cell ( paracrine stimulation).…”

Section: The Pi3k-akt and Ras-erk Pathways As Examples Of Oncogenic Smentioning

confidence: 99%

Signal Transduction in Cancer

Grainger

Brugge

2015

Cold Spring Harbor Perspectives in Medicine

757

455

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SUMMARYCancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.

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Section: The Pi3k-akt and Ras-erk Pathways As Examples Of Oncogenic Smentioning

confidence: 99%

Signal Transduction in Cancer

Grainger

Brugge

2015

Cold Spring Harbor Perspectives in Medicine

757

455

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“…Proteolytically active ADAM10 acts as an ectodomain sheddase, which releases extracellular regions of membrane-bound proteins (e.g., adhesion molecules, growth factors, cytokines, chemokines and receptors). Through these actions it is able to sculpt the tumor microenvironment and modulate key processes involved in cancer progression, including cell proliferation, migration and angiogenesis (19). The emerging role of ADAM10 as a significant contributor to these pathologies has led to its intense interest as a potential drug target for tumor treatment (6).…”

Section: Introductionmentioning

confidence: 99%

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

Shao

Shi

2013

Oncology Reports

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Abstract.The overexpression of A disintegrin and metalloproteinase 10 (ADAM10) has been found to be closely associated with the development and progression of various types of tumors. However, ADAM10 expression in hepatocellular carcinoma (HCC) and its significance remain largely unknown. The present study aimed to investigate the expression of ADAM10 in human HCC and the effect of ADAM10 gene silencing by siRNA on the proliferation, invasion and migration of HepG2 human hepatoma cells. Immunohistochemistry was performed to examine the expression of ADAM10 in human HCC tissues and in the adjacent non-cancer tissues from 30 patients with HCC. RNA interference was used to knock down ADAM10 expression in HepG2 human hepatoma cells and the proliferation and migration as well as the invasive ability of the treated cells were observed in vitro. The expression of ADAM10 protein in HCC tissues was significantly higher when compared to that in adjacent non-tumor tissues (P<0.05). The high expression of ADAM10 in cancer was significantly correlated with clinical outcomes (P<0.05). Silencing of ADAM10 resulted in inhibition of proliferation and migration as well as invasion of HepG2 human hepatoma cells (P<0.05). These studies suggest that ADAM10 plays an important role in regulating proliferation, invasion and migration of HepG2 cells. High expression of ADAM10 may be a valuable predictive factor for HCC prognosis, and ADAM10 is potentially an important therapeutic target for the prevention of tumor development and progression in HCC.

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“…Dysregulated expression of ADAM proteins has been reported in multiple tumors. These proteases are implicated as positive regulators in tumor cell proliferation, angiogenesis, and metastasis (35). Importantly, both ADAM10 and ADAM17 have been shown to be overexpressed in melanoma (36)(37)(38)(39).…”

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confidence: 99%

Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase

Qiu

Tang

et al. 2015

Molecular and Cellular Biology

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Notch1 is an evolutionarily conserved transmembrane receptor involved in melanoma growth. Notch1 is first cleaved by furin in the Golgi apparatus to produce the biologically active heterodimer. Following ligand binding, Notch1 is cleaved at the cell membrane by proteases such as ADAM10 and -17 and membrane type 1 matrix metalloproteinase (MT1-MMP), the latter of which we recently identified as a novel protease involved in Notch1 processing. The final cleavage is ␥-secretase dependent and releases the active Notch intracellular domain (NIC). We now demonstrate that Notch1 directly regulates furin expression. Aside from activating Notch1, furin cleaves and activates several proteases, including MT1-MMP, ADAM10, and ADAM17. By chromatin immunoprecipitation and a reporter assay, we demonstrate that Notch1 binds at position ؊1236 of the furin promoter and drives furin expression. The Notch1-dependent enhancement of furin expression increases the activities of MT1-MMP and ADAM10 but not that of ADAM17, as demonstrated by short hairpin RNA (shRNA) knockdown of furin, and promotes the cleavage of Notch1 itself. These data highlight a novel positive-feedback loop whereby Notch1-dependent furin expression can induce Notch1 signaling by increasing Notch1 processing and by potentiating the activity of the proteases responsible for Notch1 activation. This leads to Notch1 signal amplification, which can promote melanoma tumor growth and progression, as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1. Disruption of such feedback signaling might represent an avenue for the treatment of melanoma. Melanoma is the deadliest form of skin cancer, causing approximately 50,000 deaths a year, despite promising new therapies (1-3). It is imperative to understand the biology of melanoma in order to find novel therapeutic targets.Notch proteins are transmembrane receptors of approximately 300 kDa. In humans, there are four Notch receptors, Notch1 to Notch4, which share the same basic structure: (i) an extracellular domain, containing an epidermal growth factor-like repeat domain (EGF repeats), a LIN12-Notch repeat (LNR) domain, and a heterodimerization (HD) domain, and (ii) an intracellular domain, containing an RBP-JK (recombination signal-binding protein 1 for J)-associated module (RAM) domain, an ankyrin repeat (ANK) domain, a transactivation domain (TAD), and a PEST (proline-glutamate-serine-threonine) domain (4). Full-length Notch is first cleaved by furin in the trans-Golgi network. Such cleavage is necessary for the proper positioning of Notch1 at the plasma membrane (5, 6). Once Notch1 is at the membrane, after ligand binding, a second cleavage occurs that is canonically driven by ADAM (a disintegrin and metalloproteinase) proteases (ADAM10 and -17) (7-10). This produces an unstable fragment that is immediately cleaved by ␥-secretase to release the Notch intracellular domain (NIC) (11). The NIC translocates into the nucleus and binds with transcription factors CSL (C-promote...

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ADAMs and ADAMTSs in cancer

Cited by 34 publications

References 95 publications

Signal Transduction in Cancer

Signal Transduction in Cancer

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase

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