Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44

Hartmann, Monika; Parra, Liseth M.; Ruschel, Anne; Böhme, Sandra; Li, Yong; Morrison, Helen; Herrlich, Andreas; Herrlich, Peter

doi:10.1158/1541-7786.mcr-15-0020-t

Cited by 33 publications

(41 citation statements)

References 49 publications

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“…Some of our results need further explanation and suggest additional uncovered regulatory components. In one early study CD44 S291A was reported to inhibit cellular migration (65), while we found that it enhances CD44 cleavage, a feature that is required for migration in our hands (4). The reason for this discrepancy has yet to be uncovered.…”

Section: Discussioncontrasting

confidence: 64%

“…These data prompted us to examine the role of the ICD modifications in vivo. We already showed that cleavage of CD44 is relevant for cellular migration (4). We next tested the potential physiological role of ICD modification in neuregulin release in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1,3). This includes, for example, the biological availability of epidermal growth factor (EGF) receptor ligands such as neuregulin (NRG1) (4,5) and the modulation of complex cellular phenotypes required for contact inhibition of cells involving the hyaluronic acid receptor CD44 (4). NRG1 regulates neurite outgrowth and myelination but also has important functions in the development of other organs, for instance, the heart (6-9).…”

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confidence: 99%

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Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

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bEctodomain cleavage by A-disintegrin and -metalloproteases (ADAMs) releases many important biologically active substrates and is therefore tightly controlled. Part of the regulation occurs on the level of the enzymes and affects their cell surface abundance and catalytic activity. ADAM-dependent proteolysis occurs outside the plasma membrane but is mostly controlled by intracellular signals. However, the intracellular domains (ICDs) of ADAM10 and -17 can be removed without consequences for induced cleavage, and so far it is unclear how intracellular signals address cleavage. We therefore explored whether substrates themselves could be chosen for proteolysis via ICD modification. We report here that CD44 (ADAM10 substrate), a receptor tyrosine kinase (RTK) coreceptor required for cellular migration, and pro-NRG1 (ADAM17 substrate), which releases the epidermal growth factor (EGF) ligand neuregulin required for axonal outgrowth and myelination, are indeed posttranslationally modified at their ICDs. Tetradecanoyl phorbol acetate (TPA)-induced CD44 cleavage requires dephosphorylation of ICD serine 291, while induced neuregulin release depends on the phosphorylation of several NRG1-ICD serines, in part mediated by protein kinase C␦ (PKC␦). Downregulation of PKC␦ inhibits neuregulin release and reduces ex vivo neurite outgrowth and myelination of trigeminal ganglion explants. Our results suggest that specific selection among numerous substrates of a given ADAM is determined by ICD modification of the substrate. Many transmembrane proteins on the cell surface are subject to proteolytic cleavage of their ectodomains, predominantly by metalloproteases (ectodomain shedding) (1-3). Ectodomain shedding regulates numerous important molecules involved in signal transfer between the extracellular space and the cell's interior and thus influences many cellular functions (1, 3). This includes, for example, the biological availability of epidermal growth factor (EGF) receptor ligands such as neuregulin (NRG1) (4, 5) and the modulation of complex cellular phenotypes required for contact inhibition of cells involving the hyaluronic acid receptor CD44 (4). NRG1 regulates neurite outgrowth and myelination but also has important functions in the development of other organs, for instance, the heart (6-9). When bound to hyaluronan, CD44 triggers a proliferation-inhibitory pathway (10-12). On the other hand, cancer stem cells carry CD44 (13-15), and, in this context, CD44 promotes tumor growth and metastasis (16-21), likely via alternative splice forms of CD44 that act as growth factor-enriching coreceptors for receptor tyrosine kinases (RTKs) (22,23).Inappropriate proteolysis of a number of shed substrates is associated with diseases when cleavage is either upregulated or reduced (24, 25). Equally, total knockout of substrates leads to significant phenotypes (26,27). This indicates that ectodomain cleavage requires tight regulation. How ectodomain cleavage is regulated and made substrate specific is largely unknown to date.The metallop...

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Section: Discussioncontrasting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Parra

Hartmann

Schubach

et al. 2015

Molecular and Cellular Biology

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“…Cleaved HBEGF binds and activates ERBB4, which signals for cell survival (Hilliard et al, 2011) (Figure 3E). An additional link between CD44v6, proteases and apoptosis resistance relies on CD44v6 ectodomain cleavage by MMP9 and ADAM10 (Kim and Jung, 2012; Hartmann et al, 2015), where CD44-associated MMP14 accounts for proMMP9 cleavage and activation (Tjwa et al, 2008). Finally, CD44-dependend apoptosis resistance can proceed via CD44-promoted MMP9 expression (Desai et al, 2009), high CD44 and MMP9 expression being associated with a poor prognosis in CLL patients (Kivisaari et al, 2010; Buggins et al, 2011).…”

Section: Linking Cd44/cd44v6 Activities To Cic Featuresmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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“…Thus, only a small proportion (ϳ15%) of CD44 molecules is subject to cleavage (78), whereas the association between ADAMs and neuregulin-1 may approach 100% (77). It is remarkable that in many scores of experiments, the proportion of single-chain TSHR on the cell surface persists in the 30 -50% range (for example, see Ref.…”

Section: Regulation Of the Interaction Between Adams And The Tshrmentioning

confidence: 99%

TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective

Rapoport

McLachlan

2016

Endocrine Reviews

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The TSH receptor (TSHR) on the surface of thyrocytes is unique among the glycoprotein hormone receptors in comprising two subunits: an extracellular A-subunit, and a largely transmembrane and cytosolic B-subunit. Unlike its ligand TSH, whose subunits are encoded by two genes, the TSHR is expressed as a single polypeptide that subsequently undergoes intramolecular cleavage into disulfide-linked subunits. Cleavage is associated with removal of a C-peptide region, a mechanism similar in some respects to insulin cleavage into disulfide linked A-and B-subunits with loss of a C-peptide region. The potential pathophysiological importance of TSHR cleavage into A-and B-subunits is that some A-subunits are shed from the cell surface. Considerable experimental evidence supports the concept that A-subunit shedding in genetically susceptible individuals is a factor contributing to the induction and/or affinity maturation of pathogenic thyroid-stimulating autoantibodies, the direct cause of Graves' disease. The noncleaving gonadotropin receptors are not associated with autoantibodies that induce a "Graves' disease of the gonads." We also review herein current information on the location of the cleavage sites, the enzyme(s) responsible for cleavage, the mechanism by which A-subunits are shed, and the effects of cleavage on receptor signaling.

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Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44

Cited by 33 publications

References 49 publications

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective

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