Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation

Xu, Pinglong; Derynck, Rik

doi:10.1016/j.molcel.2010.01.034

Cited by 230 publications

(244 citation statements)

References 45 publications

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“…Cellular regulation of ADAM17 shedding activity is a complex process modulated by the ADAM17 redox state (18), protein processing (19), signal transduction pathways downstream of PKC (20), and binding to the naturally occurring ADAM17 antagonist protein TIMP3 (21). ADAM17 sheddase activity is stimulated by the PKC mimetic PMA.…”

Section: Resultsmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well in as a focused set of head and neck patient-derived xenograft models. The antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in the OE21 esophageal model and the COLO205 colorectal model suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates that function outside of the HER pathways and may contribute toward the antitumor activity of the monoclonal antibody.

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Section: Resultsmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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“…We investigated whether the intracellular domain of ADAM17 plays a role in S1P-induced breast CSC proliferation. ADAM17 activity is regulated by phosphorylation-dependent mechanisms [29][30][31] ; therefore, we generated ADAM17 mutants with either Thr735 (p38MAPK consensus motif) or Thr761 (Akt consensus motif) replaced by alanine (Fig. 4a).…”

Section: S1p Increases Adam17 Activity Without Notch Ligandsmentioning

confidence: 99%

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

et al. 2014

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Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion. Stimulation with S1P enhances ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation. CSCs overexpressing sphingosine kinase 1 (SphK1), an S1P-producing enzyme, show increased ability to develop tumours in nude mice, compared with parent cells or CSCs. Tumorigenicity of CSCs overexpressing SphK1 is inhibited by S1PR3 knockdown or S1PR3 antagonist. Breast cancer patient-derived mammospheres contain SphK1 þ /ALDH1 þ cells or S1PR3 þ /ALDH1 þ cells. Our findings provide new insights into the lipid-mediated regulation of CSCs via Notch signalling, and rationale for targeting S1PR3 in cancer.

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“…In response to signals, the TACE cytoplasmic tail is phosphorylated by kinases, including extracellular-signal-regulated kinase (ERK), and this has been suggested to enhance TACE trafficking (Fan et al 2003;Soond et al 2005;Xu and Derynck 2010). Some studies, however, have reported that the TACE tail is dispensable for signaling (Horiuchi et al 2007a).…”

Section: Tace Trafficking Regulatorsmentioning

confidence: 99%

Regulation of Receptor Tyrosine Kinase Ligand Processing

Adrain

Freeman

2014

Cold Spring Harbor Perspectives in Biology

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A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.C ells must talk to one another. This principle applies throughout the tree of life: from unicellular bacteria, to the trillions of cells that coordinate to make a mammal. Communication between cells requires dedicated machinery, capable of relaying information across membranes. Transmembrane proteins are therefore essential for signaling. Understanding how this is regulated is paramount. In mammals, receptor tyrosine kinases (RTKs) and their ligands are important examples of such machinery (Schlessinger 2000), controlling many biological processes including development, immunity, tissue repair, and metabolic homeostasis (Ullrich and Schlessinger 1990). They are transmembrane proteins with an extracellular ligand-binding motif and an intracellular kinase domain. As discussed in other chapters, a common mode of RTK activation involves receptor dimerization induced by ligand binding (Lemmon and Schlessinger 2010).Regulated access of ligand to receptor, over distance and time, is key to controlling signaling. Ligands are frequently synthesized as transmembrane forms; when they remain membrane-tethered and cannot diffuse, the range over which they can operate is limited to adjacent cells (Massague and Pandiella 1993; Singh and 1 Present address: Instituto

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Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation

Cited by 230 publications

References 45 publications

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

Regulation of Receptor Tyrosine Kinase Ligand Processing

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