Pervanadate activation of intracellular kinases leads to tyrosine phosphorylation and shedding of syndecan-1

Reiland, Jane; Ott, Vanessa; Lebakken, Connie S.; Yeaman, Charles; McCarthy, James B.; Rapraeger, Alan C.

doi:10.1042/bj3190039

Cited by 106 publications

(85 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings added further proof that the up-regulation of L1 release by PMA and pervanadate was independent of the cytoplasmic tail or its phosphorylation. The data are in agreement with findings from other shedding processes like ␤-amyloid precursor protein (47) or syndecan-1 (48) where the presence of the cytoplasmic tail is not required for up-regulation.…”

Section: Role Of Adams In L1supporting

confidence: 82%

“…Similar observations have been made before for the metalloproteinase-dependent shedding of the cell surface proteoglycan syndecan (48,51). The induction of L1 shedding by pervanadate and the EDTA-mediated detachment were similar as they were accompanied with drastic changes of the cytoskeleton and activation of the Src kinase Fyn in AR cells.…”

Section: Fig 7 Functional Characterization Of Shed L1supporting

confidence: 68%

See 1 more Smart Citation

Role of Src Kinases in the ADAM-mediated Release of L1 Adhesion Molecule from Human Tumor Cells

Gutwein

Oleszewski

Mechtersheimer

et al. 2000

Journal of Biological Chemistry

167

156

View full text Add to dashboard Cite

The ectodomain of certain transmembrane molecules can be released by proteolysis, and the solubilized antigens often exert important biological functions. We demonstrated before that the L1 adhesion molecule is shed from the cell surface. Here we show that L1 release in AR breast carcinoma cells is mediated by a member of the disintegrin metalloproteinase (ADAM) family of proteinases. Up-regulation of L1 shedding by phorbol ester or pervanadate involved distinct mechanisms. Pervanadate induced shedding and rounding-up of cells from the substrate, which was blocked by the Src kinase inhibitor PP2. Tyr phosphorylation of the L1 cytoplasmic tail and the Src kinase Fyn was observed following pervanadate treatment. Up-regulation of L1 release and activation of Fyn occurred also when cells were detached by EDTA suggesting that the regulation of L1 shedding by this pathway was linked to cell morphology and adhesion. The phorbol 12-myristate 13-acetate-induced shedding was inhibited by the protein kinase C inhibitor bisindolylmaleimide I and by PD98059, a specific inhibitor of the mitogen-activated protein kinase pathway. Soluble L1 binds to the proteoglycan neurocan and in bound form could support integrin-mediated cell adhesion and migration. We propose that the release of cell-associated adhesion molecules such as L1 may be relevant to promote cell migration.Many transmembrane proteins can undergo cleavage and release of their ectodomain into the medium (for review see Refs. 1-3). These proteins are diverse in structure and function and comprise molecules such as TNF-␣ 1 (4 -8), FasL (9), interleukin-6 receptor (10, 11), L-selectin (12-14), pro-TGF-␣, and the ␤-amyloid precursor protein (15-17). Although there is evidence for a physiological function of many released molecules, a general significance for ectodomain shedding is still disputed (2). Recently, members of the ADAM metalloproteinase family, which are membrane proteins composed of a disintegrin and metalloproteinase domain, were shown to be important in ectodomain release (for review see Refs. 3 and 18). TACE/ADAM17 mediates the membrane release of TNF-␣, Lselectin, TGF-␣ (8), and TRANCE (tumor necrosis factor-related activation-induced cytokine), a TNF family member involved in osteoclastogenesis and dendritic cell survival (19). ADAM10/Kuz has been described as an ␣-secretase for the cleavage of ␤-amyloid precursor protein (20), and ADAM9 is involved in the phorbol ester-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) (21, 22). Certain released molecules can be cleaved by more than one enzyme, and some enzymes can cleave more than one substrate. For example, TNF-␣ cleavage can also be mediated by ADAM10 (23), and ␣-secretase activity for ␤-amyloid precursor protein has been attributed to TACE/ADAM17 (24) and ADAM9 (25). It is not known how the protease(s) select their substrate, because consensus cleavage sites have not been identified. In addition to the proteolytic function, some members of the ADAM famil...

show abstract

Section: Role Of Adams In L1supporting

confidence: 82%

Section: Fig 7 Functional Characterization Of Shed L1supporting

confidence: 68%

Role of Src Kinases in the ADAM-mediated Release of L1 Adhesion Molecule from Human Tumor Cells

Gutwein

Oleszewski

Mechtersheimer

et al. 2000

Journal of Biological Chemistry

167

156

View full text Add to dashboard Cite

show abstract

“…In other cases, the main function of syndecan binding might be to mediate internalization and possible degradation of the bound proteins. Heparan sulphate-dependent internalization of several extracellular ligands has been reported, including bFGF, lipoprotein lipase and thrombospondin [142,[151][152][153]. There is evidence that the kinetics of internalization and final destinations of ligands that utilize this pathway are distinct from those mediated by more conventional internalization pathways.…”

Section: Other Ligandsmentioning

confidence: 99%

Syndecans: multifunctional cell-surface co-receptors

Carey

1997

Biochemical Journal

621

497

View full text Add to dashboard Cite

This review will summarize our current state of knowledge of the structure, biochemical properties and functions of syndecans, a family of transmembrane heparan sulphate proteoglycans. Syndecans bind a variety of extracellular ligands via their covalently attached heparan sulphate chains. Syndecans have been proposed to play a role in a variety of cellular functions, including cell proliferation and cell–matrix and cell–cell adhesion. Syndecan expression is highly regulated and is cell-type- and developmental-stage-specific. The main function of syndecans appears to be to modulate the ligand-dependent activation of primary signalling receptors at the cell surface. Principal functions of the syndecan core proteins are to target the heparan sulphate chains to the appropriate plasma-membrane compartment and to interact with components of the actin-based cytoskeleton. Several functions of the syndecans, including syndecan oligomerization and actin cytoskeleton association, have been localized to specific structural domains of syndecan core proteins.

show abstract

“…Because the putative 38-amino acid syndecan 3 ICD we detected runs at 7 kDa and syndecan 3 CFT runs at 10 -12 kDa in SDS-gels, these fragments as well may exist as dimers. Alternatively, low electrophoretic mobility might be due to phosphorylation of highly conserved serine or tyrosine residues (10). Dimerization of other syndecans has not been addressed systematically, but the demonstration of a 6-kDa syndecan 1 CFT argues in favor of a monomeric syndecan 1 CTF (10).…”

Section: Fig 4 Luciferase Assay To Quantify Sicd Generation In Hek2mentioning

confidence: 99%

Syndecan 3 Intramembrane Proteolysis Is Presenilin/γ-Secretase-dependent and Modulates Cytosolic Signaling

Schulz

Annaert

Vandekerckhove

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The syndecans play critical roles in several signal transduction pathways. The core proteins of these heparan sulfate proteoglycans are characterized by highly conserved transmembrane and intracellular domains which are required for signaling across the membrane and for interaction with cytosolic proteins. However, regulatory mechanisms controlling these functions remain largely unknown. Here we show that, upon ligandinduced primary proteolytic cleavage within the ectodomain, the intracellular domain of syndecan 3 is released by regulated intramembrane proteolysis. The cleavage is mediated by presenilin/␥-secretase complex and negatively regulates the plasma membrane targeting of the transcriptional cofactor CASK.Heparan sulfate proteoglycans (HSPG) 1 are present on the surface of all adherent cells. Binding to a large number of ligands depends upon highly charged heparan sulfate chains, linear polysaccharide chains that can be modified by sequential enzymatic modifications. These modifications lead to enormous structural diversity (for review see Ref. 1). Although numerous functions for the heparan sulfate moiety of proteoglycans have been shown in vivo and in vitro, the roles of the core proteins remain largely elusive (2, 3). The syndecan family of HSPG, as opposed to the GPI-anchored glypicans or matrix-associated HSPG, contains a transmembrane and cytosolic domain that is highly conserved across homologues and species, suggesting an important role for this part of the protein (4). Indeed, a role in FGF signaling, neurite outgrowth, dendritic spine morphogenesis, and left-right axis formation has been demonstrated (5-8), but the regulatory mechanisms are incompletely understood. The cytosolic domain can be subdivided into a membrane-proximal C1 and a C-terminal C2 conserved region that is nearly identical in all syndecans and has a more variable V region in the middle. The most conserved residues are serines and tyrosines that at least partially undergo phosphorylation, a basic motif that binds nonreceptor tyrosine kinases and cytoskeletal proteins, and the C terminus that is required for interaction with PDZ proteins such as syntenin, CASK, synectin, or synbindin (for review see Ref. 4).The heparan sulfate-bearing syndecan ectodomain has been shown to undergo ligand-activated or stress-induced proteolytic cleavage and shedding (9 -11), but the fate of the Cterminal fragment (CTF) that remains associated with the membrane is unknown. We surmised that the remaining CTF is subject to further proteolytic degradation, ectodomain-shedding being a first step in an intracellular signaling cascade. Because regulated intramembrane proteolysis, a novel mechanism of signal transduction across the membrane (12), has been demonstrated to depend upon prior ectodomain cleavage of type I transmembrane protein substrates (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) and is mediated by presenilins (PS) as part of a larger so-called ␥-secretase complex (23), we investigated whether syndecan 3 undergoes PS-dependent cleavage. EXPERI...

show abstract

Pervanadate activation of intracellular kinases leads to tyrosine phosphorylation and shedding of syndecan-1

Cited by 106 publications

References 54 publications

Role of Src Kinases in the ADAM-mediated Release of L1 Adhesion Molecule from Human Tumor Cells

Role of Src Kinases in the ADAM-mediated Release of L1 Adhesion Molecule from Human Tumor Cells

Syndecans: multifunctional cell-surface co-receptors

Syndecan 3 Intramembrane Proteolysis Is Presenilin/γ-Secretase-dependent and Modulates Cytosolic Signaling

Contact Info

Product

Resources

About