Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα

Horowitz, Arie; Simons, Michael

doi:10.1074/jbc.273.40.25548

Cited by 120 publications

(137 citation statements)

References 16 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Syn4 interacts with PIP 2 , and this stabilises the oligomeric structure of Syn4 and promotes the association of PKCα and Syn4 (Oh et al, 1997a;Oh et al, 1997b;Horowitz and Simons, 1998;Lim et al, 2003); the catalytic domain of PKCα binds to the cytoplasmic domain of Syn4, and PKCα is 'superactivated' (Lim et al, 2003;Murakami et al, 2002). This interaction between PKCα and Syn4 provides a satisfactory explanation for our observation that neural induction by Syn4 requires PKCα and vice versa.…”

Section: Discussionsupporting

confidence: 47%

“…As Syn4 also interacts with fibronectin and integrins and is required for the formation of focal adhesions (Woods and Couchman, 2001), its main role has been thought to be in cell migration. However, Syn4 is also able to modulate PKC-and small GTPase-dependent intracellular signalling (Bass et al, 2007;Horowitz et al, 1999;Horowitz and Simons, 1998;Keum et al, 2004;Matthews et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways

Kuriyama

Mayor

2009

Development

View full text Add to dashboard Cite

Syndecan-4 (Syn4) is a heparan sulphate proteoglycan that is able to bind to some growth factors, including FGF, and can control cell migration. Here we describe a new role for Syn4 in neural induction in Xenopus. Syn4 is expressed in dorsal ectoderm and becomes restricted to the neural plate. Knockdown with antisense morpholino oligonucleotides reveals that Syn4 is required for the expression of neural markers in the neural plate and in neuralised animal caps. Injection of Syn4 mRNA induces the cellautonomous expression of neural, but not mesodermal, markers. We show that two parallel pathways are involved in the neuralising activity of Syn4: FGF/ERK, which is sensitive to dominant-negative FGF receptor and to the inhibitors SU5402 and U0126, and a PKC pathway, which is dependent on the intracellular domain of Syn4. Neural induction by Syn4 through the PKC pathway requires inhibition of PKCδ and activation of PKCα. We show that PKCα inhibits Rac GTPase and that c-Jun is a target of Rac. These findings might account for previous reports implicating PKC in neural induction and allow us to propose a link between FGF and PKC signalling pathways during neural induction.

show abstract

Section: Discussionsupporting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways

Kuriyama

Mayor

2009

Development

View full text Add to dashboard Cite

show abstract

“…Recent studies have suggested that syndecan-4 plays an important role in regulation of endothelial cell growth and migration and in basic fibroblast growth factor-dependent signaling (4,5,7). Studies in our laboratory have suggested that increased syndecan-4 expression augmented the ability of endothelial cells to migrate, proliferate, and form vascular structures in Matrigel in response to basic fibroblast growth factor.…”

Section: Discussionmentioning

confidence: 77%

Myocyte-dependent Regulation of Endothelial Cell Syndecan-4 Expression

Zhang

Pasparakis

Kollias

et al. 1999

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Syndecan-4 is a unique member of the syndecan gene family that has the ability to bind and activate protein kinase C-␣. Whereas increased syndecan-4 levels have been noted in ischemic hearts, little is known regarding the regulation of its expression. To investigate the role of cardiac myocytes in induction of syndecan-4 expression, human endothelial cells (ECV304) were exposed to a medium conditioned by primary mouse cardiac myocytes or H9c2 cells. The medium conditioned by hypoxic but not normal myocytes was able to induce syndecan-4 expression in ECV cells. Western analysis of the conditioned medium demonstrated an increased presence of tumor necrosis factor-␣ (TNF-␣) in the medium conditioned by hypoxic but not normal myoblasts. Primary cardiac myocytes collected from the wild type C57/129 but not the homozygous TNF-␣ ؊/؊ knockout mice were able to induce syndecan-4 expression in ECV cells when cultured under hypoxic conditions. In vitro studies demonstrated that TNF-␣ induced endothelial cell syndecan-4 expression by both increasing syndecan-4 gene expression in an NF-B-dependent manner and by prolonging syndecan-4 mRNA half-life. We conclude that TNF-␣ is the principal factor produced by the ischemic myocytes that is responsible for induction of endothelial cell syndecan-4 expression and that this requires both transcriptional and posttranscriptional mechanisms.Syndecan-4 is one of the principal heparin sulfate-carrying proteins on the cell surface (1). It is expressed by a number of different cell types including endothelial cells, smooth muscle cells, and cardiac myocytes, although expression in quiescent tissues is fairly low. Syndecans can participate in a variety of biological functions including regulation of blood coagulation, cell adhesion, and low density lipoprotein transport (2, 3). In addition to these activities shared by all syndecans, syndecan-4 cytoplasmic domain can bind to and activate protein kinase C-␣ with the degree of activation regulated by the extent of syndecan-4 cytoplasmic tail phosphorylation (4 -7).Despite these interesting properties, little is known about the regulation of syndecan-4 gene expression. Its levels are increased after various forms of tissue injury including skin wounds (8), vascular wall injury (9), or myocardial infarction (10). The increase in syndecan-4 expression in skin wounds and in the heart following myocardial infarction has been ascribed to the presence of a proline-arginine-rich peptide, PR39. No other factors responsible for this increase have been identified (8, 10). The present study was designed to study the role of cardiac myocytes in the induction of syndecan-4 expression under normal and ischemic (hypoxic) conditions. To this end, we determined the ability of myocyte-or myoblast-conditioned medium to induce syndecan-4 expression in a human endothelial cell line. We find that TNF-␣ 1 secreted by hypoxic but not normal myocytes is able to induce syndecan-4 expression and that the mechanism of this induction involves both transcriptional activati...

show abstract

“…The fact that some of these studies have been performed with NG2-negative cells makes it clear that targets other than NG2 play key roles in PKC-␣-induced cell migration. Among proteoglycans, for example, PKC-mediated phosphorylation of CD44 (1) and syndecans (52)(53)(54) plays essential roles in regulating changes in cell morphology. In the case of U251 cells, PMA is capable of inducing polarization and motility in the NG2-negative parental cells.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of NG2 Proteoglycan by Protein Kinase C-α Regulates Polarized Membrane Distribution and Cell Motility

Makagiansar

Williams

Dahlin-Huppe

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Protein kinase C (PKC)-␣ phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr 2256 , identifying this residue as a primary phosphorylation site. In untreated U251/NG2 cells, NG2 is present along with ezrin and ␣ 3 ␤ 1 integrin in apical cell surface protrusions. Phorbol ester treatment causes redistribution of all three components to lamellipodia, accompanied by increased cell motility. U251 cells expressing NG2 with a valine substitution at position 2256 are resistant to phorbol ester treatment: NG2 remains in membrane protrusions and cell motility is unchanged. In contrast, NG2 with a glutamic acid substitution at position 2256 redistributes to lamellipodia even without phorbol ester treatment, rendering transfected U251 cells spontaneously motile. PKC-␣-mediated NG2 phosphorylation at Thr 2256 is therefore a key step for initiating cell polarization and motility.Transmembrane proteoglycans such as CD44 and syndecans make important contributions to communication between the exterior and interior of the cell (1, 2). We are elucidating specific signaling functions for NG2, a membrane-spanning chondroitin sulfate proteoglycan found on several types of immature progenitor cells and on a variety of tumor types (3). Two hallmarks of both progenitor and tumor cells are increased motility and proliferation, both of which are influenced by NG2 (4 -7).Several mechanisms have been suggested to account for the contribution of NG2 to these processes. These include sequestration of growth factors (5, 8), modulation of the activity of kringle domain proteins (9, 10) and matrix metalloproteinases (11), and interaction with other cell surface molecules or with extracellular matrix components that regulate signaling pathways involved in cell proliferation and motility (12-15). NG2 engagement has been shown to result in activation of the small GTPases cdc42 and rac (15, 16) and in ␤ 1 integrin-dependent activation of focal adhesion kinase and ERK-1/2 1 (17, 18). The fundamental importance of these pathways in cell physiology underscores the potential significance of elucidating the specific contributions of NG2 to transmembrane communication.Protein phosphorylation and dephosphorylation are recognized as critical aspects of intracellular signaling. By altering protein conformation and by creating docking sites for proteinprotein interaction, phosphorylation and dephosphorylation of cytoplasmic tyrosine, serine, and threonine residues provide an extremely versatile means of regulating signaling pathways (19,20). Although the NG2 cytoplasmic domain contains several threonine residues that might serve as phosphorylation sites (21), to date we have had no experimental verification of this type of modification in NG2 and no information about potential functional consequences. The current work sheds initial light on these questions by identifying Thr 2256 as the primary site for NG2 modification by PK...

show abstract

Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα

Cited by 120 publications

References 16 publications

A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways

A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways

Myocyte-dependent Regulation of Endothelial Cell Syndecan-4 Expression

Phosphorylation of NG2 Proteoglycan by Protein Kinase C-α Regulates Polarized Membrane Distribution and Cell Motility

Contact Info

Product

Resources

About