Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

Minder, Petra; Bayha, Elke; Becker‐Pauly, Christoph; Sterchi, Erwin E.

doi:10.1074/jbc.m112.368910

Cited by 33 publications

(33 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides HCC, there is only limited evidence for a role of meprin α in cell proliferation. A single study has shown that recombinant meprin α could stimulate colorectal cancer cell proliferation via the transactivation of the EGF receptor [11]. In addition, others have shown that the meprin inhibitor actinonin reduced the growth of a large number of tumor cell lines, a finding that we also observed with HCC cells (data not shown).…”

Section: Discussionsupporting

confidence: 77%

Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin

et al. 2016

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinoma is associated with a high rate of intra-hepatic invasion that carries a poor prognosis. Meprin alpha (Mep1A) is a secreted metalloproteinase with many substrates relevant to cancer invasion. We found that Mep1A was a target of Reptin, a protein that is oncogenic in HCC. We studied Mep1A regulation by Reptin, its role in HCC, and whether it mediates Reptin oncogenic effects.MepA and Reptin expression was measured in human HCC by qRT-PCR and in cultured cells by PCR, western blot and enzymatic activity measurements. Cell growth was assessed by counting and MTS assay. Cell migration was measured in Boyden chambers and wound healing assays, and cell invasion in Boyden chambers.Silencing Reptin decreased Mep1A expression and activity, without affecting meprin β. Mep1A, but not meprin β, was overexpressed in a series of 242 human HCC (2.04 fold, p < 0.0001), and a high expression correlated with a poor prognosis. Mep1A and Reptin expressions were positively correlated (r = 0.39, p < 0.0001). Silencing Mep1A had little effect on cell proliferation, but decreased cell migration and invasion of HuH7 and Hep3B cells. Conversely, overexpression of Mep1A or addition of recombinant Mep1A increased migration and invasion. Finally, overexpression of Mep1A restored a normal cell migration in cells where Reptin was depleted.Mep1A is overexpressed in most HCC and induces HCC cell migration and invasion. Mep1A expression is regulated by Reptin, and Mep1A mediates Reptin-induced migration. Overall, we suggest that Mep1A may be a useful target in HCC.

show abstract

Section: Discussionsupporting

confidence: 77%

Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…We identified meprin α as the first soluble metalloprotease that can shed the IL-6R. Interestingly, meprin α was previously shown to cleave and release some ligands of the EGFR17, additionally demonstrating a partially overlapping substrate repertoire with ADAM10/17. On the other hand, meprin β membrane tethering appears to be a prerequisite for IL-6R shedding, because the soluble protease did not result in receptor cleavage.…”

Section: Discussionmentioning

confidence: 94%

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Arnold

Boll

Rothaug

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.

show abstract

“…This cleavage is stimulated by endotoxins (Breshears et al, 2012; Liu Z. et al, 2013) and ROS (Boots et al, 2009) and is mediated primarily by ADAM17 (Peschon et al, 1998), but also by ADAM10 (Hinkle et al, 2003) and MeprinA (Bergin et al, 2008; Minder et al, 2012; Singh and Coffey, 2014). Moreover, TGF-α can interact with and activate EGFR on neighboring cells (Schlessinger and Ullrich, 1992; Thorne and Plowman, 1994; Moral et al, 2001).…”

Section: Tetraspanins and Receptor-mediated Signalingmentioning

confidence: 99%

Tetraspanins Function as Regulators of Cellular Signaling

Termini

Gillette

2017

Front. Cell Dev. Biol.

223

186

View full text Add to dashboard Cite

Tetraspanins are molecular scaffolds that distribute proteins into highly organized microdomains consisting of adhesion, signaling, and adaptor proteins. Many reports have identified interactions between tetraspanins and signaling molecules, finding unique downstream cellular consequences. In this review, we will explore these interactions as well as the specific cellular responses to signal activation, focusing on tetraspanin regulation of adhesion-mediated (integrins/FAK), receptor-mediated (EGFR, TNF-α, c-Met, c-Kit), and intracellular signaling (PKC, PI4K, β-catenin). Additionally, we will summarize our current understanding for how tetraspanin post-translational modifications (palmitoylation, N-linked glycosylation, and ubiquitination) can regulate signal propagation. Many of the studies outlined in this review suggest that tetraspanins offer a potential therapeutic target to modulate aberrant signal transduction pathways that directly impact a host of cellular behaviors and disease states.

show abstract

Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

Cited by 33 publications

References 58 publications

Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin

Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin

Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Tetraspanins Function as Regulators of Cellular Signaling

Contact Info

Product

Resources

About