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• W2080559953 abstract "Syndecans are transmembrane proteoglycans capable of carrying both heparan and chondroitin sulfate chains. The cytoplasmic tail of syndecan-4 was recently reported to undergoin vivo phosphorylation on Ser183 in the membrane-proximal part of the tail (Horowitz, A., and Simons, M. (1998)J. Biol. Chem. 273, 10914–10918). However, the functional consequences of this event remain unknown. The cytoplasmic tail of syndecan-4 is known to undergo multimerization and to activate protein kinase Cα (PKCα), with both events depending on the presence of the commonly occurring phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). In the present investigation we found that phosphorylation of Ser183 produced a 10-fold reduction in the ability of syndecan-4 to activate PKCα, without affecting its ability to bind the PKC. Because Ser183 is adjacent to positively charged lysine groups that resemble PIP2-binding regions in several other proteins, phosphorylation of this serine may affect the binding affinity of the syndecan-4 cytoplasmic tail to PIP2. We found that the Ser183-phosphorylated cytoplasmic tail of syndecan-4 has indeed a significantly lower affinity to PIP2 compared with the nonphosphorylated tail. Furthermore, Ser183phosphorylation abolished PIP2-dependent oligomerization of syndecan-4 cytoplasmic tails. We conclude that Ser183 phosphorylation regulates syndecan-4-dependent activation of PKCα by reducing the affinity to PIP2 and inhibiting the oligomerization of syndecan-4 cytoplasmic tails. These results further support the role of syndecan-4 in signal transduction in endothelial cells. Syndecans are transmembrane proteoglycans capable of carrying both heparan and chondroitin sulfate chains. The cytoplasmic tail of syndecan-4 was recently reported to undergoin vivo phosphorylation on Ser183 in the membrane-proximal part of the tail (Horowitz, A., and Simons, M. (1998)J. Biol. Chem. 273, 10914–10918). However, the functional consequences of this event remain unknown. The cytoplasmic tail of syndecan-4 is known to undergo multimerization and to activate protein kinase Cα (PKCα), with both events depending on the presence of the commonly occurring phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). In the present investigation we found that phosphorylation of Ser183 produced a 10-fold reduction in the ability of syndecan-4 to activate PKCα, without affecting its ability to bind the PKC. Because Ser183 is adjacent to positively charged lysine groups that resemble PIP2-binding regions in several other proteins, phosphorylation of this serine may affect the binding affinity of the syndecan-4 cytoplasmic tail to PIP2. We found that the Ser183-phosphorylated cytoplasmic tail of syndecan-4 has indeed a significantly lower affinity to PIP2 compared with the nonphosphorylated tail. Furthermore, Ser183phosphorylation abolished PIP2-dependent oligomerization of syndecan-4 cytoplasmic tails. We conclude that Ser183 phosphorylation regulates syndecan-4-dependent activation of PKCα by reducing the affinity to PIP2 and inhibiting the oligomerization of syndecan-4 cytoplasmic tails. These results further support the role of syndecan-4 in signal transduction in endothelial cells. heparan sulfate basic fibroblast growth factor polyacrylamide gel electrophoresis phosphatidylinositol 4,5-bisphosphate protein kinase C polyvinylidene fluoride phosphatidylserine N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine Rat fat pad capillary endothelial cell(s). Heparan sulfate (HS)1chains on the cell surface and in the extracellular matrix are present on a specific group of proteins referred to as proteoglycans, which is composed of several classes of core proteins that serve as acceptors for different glycosaminoglycan chains. Heparan sulfate proteoglycans are thought to play an important role in a number of biological processes including regulation of blood coagulation, cell adhesion, and signal transduction. These functions are largely thought to be mediated by HS chains capable of binding growth factors, cell adhesion receptors, and other biologically active molecules (1Rosenberg R.D. Shworak N.W. Liu J. Schwartz J.J. Zhang L. J. Clin. Invest. 1997; 99: 2062-2070Crossref PubMed Scopus (258) Google Scholar). Relatively little attention has been paid, however, to the function of the proteoglycan core proteins themselves. Of the three main classes of HS-carrying core proteins (syndecans, glypicans, and perlecan) only the syndecans possess a highly conserved transmembrane domain and a short cytoplasmic tail. Accumulating evidence suggests that the cytoplasmic tails of several members of the syndecan family can participate in transduction of extracellular signals into the cell. Thus, the cytoplasmic tail of syndecan-3 was reported to bind Src family tyrosine kinases and to mediate neurite growth factor signaling (2Kinnunen T. Kaksonen M. Saarinen J. Kalkkinen N. Peng H.B. Rauvala H. J. Biol. Chem. 1998; 273: 10702-10708Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). The ubiquitously expressed syndecan-4, which had been reported earlier to be incorporated into focal adhesions upon PKC stimulation (3Baciu P.C. Goetinck P.F. Mol. Biol. Cell. 1995; 6: 1503-1513Crossref PubMed Scopus (120) Google Scholar), was found more recently to bind and regulate the activity of PKC (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 5Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 8133-8136Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 6Oh E.S. Woods A. Lim S.T. Theibert A.W. Couchman J.R. J. Biol. Chem. 1998; 273: 10624-10629Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). Moreover, we have recently reported that Ser183 located in the cytoplasmic tail of syndecan-4 becomes phosphorylated upon PKC stimulation, whereas cell treatment with bFGF reduces the phosphorylation of Ser183 (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The functional effects of this phosphorylation on the molecular properties of syndecan-4 and on its signaling activity have not yet been elucidated, however. The regulation of PKC activity by syndecan-4 appears to be mediated by PIP2 (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 6Oh E.S. Woods A. Lim S.T. Theibert A.W. Couchman J.R. J. Biol. Chem. 1998; 273: 10624-10629Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar), which binds directly to the cytoplasmic tail of syndecan-4 (8Lee D. Oh E.S. Woods A. Couchman J.R. Lee W. J. Biol. Chem. 1998; 273: 13022-13029Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar) and facilitates its multimerization (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). This study addresses, therefore, the effect of phosphorylation of the cytoplasmic tail of syndecan-4 on its interaction with PIP2, as well as on its capacities to undergo multimerization and to activate PKCα. PIP2, phosphatidylserine (PS), and diolein were purchased from Sigma. Recombinant PKCα and PKCδ were synthesized and prepared as described (9Nishikawa K. Toker A. Johannes F.J. Songyang Z. Cantley L.C. J. Biol. Chem. 1997; 272: 952-960Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar). PKCβI optimal substrate peptide (FKLKRKGSFKKFA) was purchased from Tufts University Medical School (Boston, MA). A 28-amino acid-long syndecan-4 cytoplasmic tail peptide (S4c) (RMKKKDEGSYDLGKKPIYKKAPTNEFYA) was synthesized by Genemed Synthesis (South San Francisco, CA). A similar peptide with a phosphorylated Ser (S4c-P) was synthesized by the Biopolymers Laboratory, Harvard Medical School (Boston, MA). PIP2 (from Sigma, dissolved at 2 mg/ml in 20 parts CHCl3, 9 parts MeOH, 1 part H2O, 0.1 part 1 n HCl) was dried under N2 and sonicated for 5 min in ice-cold H2O at a final concentration of 1 mg/ml. Syndecan-4 cytoplasmic tail peptides S4c or S4c-P (100 μm) were incubated on ice for 30 min with the indicated concentrations of PIP2 in 10 mm Tris-HCl (pH 7.5), 75 mm KCl, 0.5 mm dithiothreitol in aliquots of 100 μl. The samples were layered on 30-kDa molecular mass cut-off cellulose filters (Ultrafree-MC, Millipore, Bedford, MA) and spun at 2000 × g for 1 min following the method described in Ref. 10Haarer B.K. Petzold A.S. Brown S.S. Mol. Cell. Biol. 1993; 13: 7864-7873Crossref PubMed Scopus (94) Google Scholar. The samples (40 μl of each in Laemmli sample buffer, 2% SDS, 10% glycerol, 0.5% β-mercaptoethanol, 0.004% bromphenol blue, 50 mm Tris-HCl, pH 6.8) were resolved by SDS-PAGE on 16.5% Tris-Tricine gels (Bio-Rad). Gels were stained with Coomassie Brilliant Blue G-250 (Bio-Rad), and images of the stained bands were digitized (DeskScan II on ScanJet 4c, Hewlett Packard) and quantitated by densitometry (ImageQuant, Molecular Dynamics, Sunnyvale, CA). Syndecan-4 cytoplasmic tail peptides S4c or S4c-P (300 μm) were incubated with PIP2 (350 μm, prepared as above) in 0.5 ml 50 mm HEPES (pH 7.3), 150 mm NaCl on ice for 30 min. Samples were applied at 4 °C to a Sephadex G-50 (Amersham Pharmacia Biotech) 30 × 1.6 cm column equilibrated with the incubation buffer, and the absorbency of the flow-through was measured at 280 nm. Rat fat pad capillary endothelial cells (RFPEC, gift of Dr. R. D. Rosenberg, MIT (11de Agostini A.I. Watkins S.C. Slayter H.S. Youssoufian H. Rosenberg R.D. J. Cell Biol. 1990; 111: 1293-1304Crossref PubMed Scopus (200) Google Scholar)) were grown to confluence in M199 medium supplemented with 10% fetal bovine serum (Life Technologies, Inc.) at 37 °C in a 5% CO2humidified atmosphere. The cells were harvested by trypsinization, lyzed, and subjected to immunoprecipitation with a cytoplasmic tail-specific antiserum (gift of Dr. N. W. Shworak, MIT (12Shworak N.W. Shirakawa M. Mulligan R.C. Rosenberg R.D. J. Biol. Chem. 1994; 269: 21204-21214Abstract Full Text PDF PubMed Google Scholar)) as described (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Immunoprecipitated syndecan-4 cytoplasmic tail was resuspended in Laemmli sample buffer and resolved by SDS-PAGE on a 4–20% Tris-glycine gel (Bio-Rad) and transferred for 2 h at 250 mA in 150 mm glycine, 20 mm Tris-HCl, and 20% methanol to a polyvinylidene fluoride (PVDF) membrane (Immobilon-P, Millipore). The membranes were immunoblotted as described (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar) using polyclonal antibodies to PKCα or to PKCδ (both at 2 μg/ml, purchased from Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic tail peptides S4c or S4c-P (10 μm) were incubated on ice for 30 min either in the presence or absence of PIP2 (20 μm, prepared as above) with recombinant PKCα (4 μm) in 0.5 ml of the same buffer used in the PIP2 binding assay. The cytoplasmic tail peptide was immunoprecipitated, and the samples were resolved by SDS-PAGE, transferred, and immunoblotted as described above. Samples (30 μl) consisted of PKCβI optimal substrate peptide (100 μm) either with or without syndecan-4 cytoplasmic tail peptides S4c or S4c-P (both at 50 μm) in 25 mm Tris-HCl (pH 7.4), 5 mm MgCl2, 1 mm dithiothreitol, 50 μm ATP, and 5 μCi of [γ-32P]ATP (NEN Life Science Products). In some assays the buffer was supplemented with either PIP2 (50 μm) or PS (4 μg/ml), diolein (6.2 μg/ml), and 0.2 mm CaCl2. In PKCδ assays the buffer was supplemented with PS and diolein as above and with 0.5 mm EGTA. Upon addition of either PKCα (120 ng/ml) or PKCδ (430 ng/ml), samples were incubated at 30 °C for 10 min, and reactions were stopped by boiling in Laemmli sample buffer for 4 min. The samples were resolved on 16.5% Tris-Tricine gels (Bio-Rad), transferred to PVDF membranes, and detected as described (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Syndecan-4 cytoplasmic tail has been shown to activate a mixture of Ca2+-dependent PKCs and of recombinant PKCα in the presence of PIP2 (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 5Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 8133-8136Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). To assess the effect of Ser183 phosphorylation on syndecan-4-dependent PKC activation, we studied the ability of the S4c and S4c-P peptides to activate recombinant PKCα using the PKCβI optimal substrate peptide (9Nishikawa K. Toker A. Johannes F.J. Songyang Z. Cantley L.C. J. Biol. Chem. 1997; 272: 952-960Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar) in an in vitro assay. When the assays were carried out with the standard cPKC cofactors PS, diacylglycerol, and calcium, the presence of neither the S4c nor the S4c-P peptides had any additional effect on the catalytic activity of PKCα (Fig. 1). That was also the case in PKC assays where no cofactors were added. However, in the presence of PIP2 together with the S4c peptide, the catalytic activity of PKCα toward the PKCβI peptide was approximately 10-fold larger than in assays with PIP2 alone. On the other hand, when the S4c-P peptide was added instead of S4c, the phosphorylation level of the substrate was similar to that obtained with PIP2 alone. Unlike PKCα, the S4c peptide did not activate PKCδ under the same conditions (data not shown). The activity of PKCα in the presence of the S4c peptide and PIP2 was 72 ± 10% (±S.D., n = 3) of its activity in the presence of the S4c peptide, PS, diacylglycerol, and calcium. The ability of the unphosphorylated but not the phosphorylated cytoplasmic tail of syndecan-4 to activate PKCα in vitro may relate to a reduced PKCα affinity upon phosphorylation of the cytoplasmic tail. Previous studies have demonstrated the ability of the cytoplasmic tail of syndecan-4 to bind PKC (5Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 8133-8136Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), and the identity of the bound PKC isozyme in vivo was narrowed down to a group of four (α, βI, βII, γ, and δ (5Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 8133-8136Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar)). Although PKCα was shown to bind to the cytoplasmic tail of syndecan-4 in vitro (5Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 8133-8136Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), the cytoplasmic tail could also bind to and be a substrate of PKCδ (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). To determine the ability of syndecan-4 to bind PKCα or δ in vivo, RFPEC lysates were immunoprecipitated with an antiserum specific to the cytoplasmic tail, and the immunoprecipitants were probed with antibodies specific either to the α or δ PKC isozymes. The presence of PKCα but not of PKCδ was detected in the immunoprecipitants (Fig. 2, Aand B). To analyze the effect of syndecan-4 cytoplasmic tail phosphorylation on its ability to bind PKCα, we carried out in vitro assays with recombinant PKCα and the S4c and S4c-P peptides. Incubation of PKCα with either peptide produced, however, similar degrees of binding both in the presence and absence of PIP2 (Fig. 2 C). It follows, therefore, that PKCα binding is not affected by the Ser183 phosphorylation in the syndecan-4 cytoplasmic tail and thus cannot explain the effect of syndecan-4 phosphorylation on the activity of the enzyme. Both the oligomerization and PKCα activation capacities of the cytoplasmic tail of syndecan-4 were found to depend on the presence of PIP2 (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 8Lee D. Oh E.S. Woods A. Couchman J.R. Lee W. J. Biol. Chem. 1998; 273: 13022-13029Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). It was of interest, therefore, to determine whether the phosphorylation of Ser183 in the cytoplasmic tail of syndecan-4 affects the affinity of the tail to PIP2. To this end, we compared thein vitro binding between PIP2 micelles and S4c or S4c-P peptides using a filtration assay. The filter retains the PIP2 micelle-bound peptide, whereas the unbound peptide passes through it. The binding affinity of the S4c peptide to PIP2, as determined by band densitometry of the SDS-PAGE-resolved filter flow-through samples, was significantly higher than that of the S4c-P peptide. At a peptide:PIP2 molar ratio of 2:1, 50% of the S4c peptide that passed through the filter in the absence of PIP2 was retained versus none of the S4c-P peptide (Fig. 3). Practically all the applied S4c peptide was retained by the filter at a peptide:PIP2 molar ratio of 1:2, whereas as much as 50% of the S4c-P peptide still passed through the filter under the same conditions. The apparent dissociation constants (K d) calculated from the results shown in Fig. 3 were 2.4 μmfor the nonphosphorylated peptide (S4c), versus 232 μm for the phosphorylated one (S4c-P). Thus, Ser183 phosphorylation results in significant reduction in the ability of PIP2 to bind to the cytoplasmic tail of syndecan-4. Previous studies have demonstrated that the cytoplasmic tail of syndecan-4 undergoes oligomerization in the presence of PIP2 (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 8Lee D. Oh E.S. Woods A. Couchman J.R. Lee W. J. Biol. Chem. 1998; 273: 13022-13029Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar); furthermore this oligomerization appeared necessary for PKCα activation. The reduced affinity between the cytoplasmic tail and PIP2 caused by phosphorylation could conceivably be accompanied by changes in the oligomerization properties of syndecan-4. To compare the oligomerization of the S4c peptide to that of the phosphorylated peptide S4c-P, both were incubated either in the presence or absence of PIP2 as described under “Experimental Procedures” and passed through a size exclusion column. Both peptides eluted as a single peak when incubated in the absence of PIP2 (Fig. 4, A and B). When incubated in the presence of PIP2, the S4c peptide eluted as two peaks, one of an approximate molecular mass of 7 kDa (Fig. 4 C), and another heavier peak of a molecular mass greater than 17 kDa (the molecular mass of the heaviest molecular mass standard used in this experiment). The S4c-P peptide, on the other hand, eluted as a single peak of the same approximate molecular mass as the first peak of the S4c peptide (Fig. 4 D). These results indicate that the cytoplasmic tail of syndecan-4 looses its capacity to form oligomers upon phosphorylation of Ser183. Based on the position of the first peaks of the S4c and the S4c-P peptides, it appears that both the S4c (as previously reported (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar)) and the S4c-P peptides formed dimers, similar to the behavior observed in the PIP2-binding experiment (Fig. 3). The broader peaks observed with both peptides when incubated in the presence of PIP2, compared with the sharper ones obtained in the absence of PIP2, reflect a wider spread in molecular mass, probably resulting from the range of PIP2 binding to the peptides. This study presents three distinct findings concerning the role of the syndecan-4 core protein in signal transduction: (a) Phosphorylation of a single serine residue (Ser183) located in the membrane-proximal part of the cytoplasmic tail of syndecan-4 reduces the affinity of the tail to the phosphoinositide PIP2. Upon phosphorylation, the cytoplasmic tail loses its capacity to (b) undergo multimerization and (c) activate PKCα in the presence of PIP2. These findings provide the first evidence for a functional role of the recently reported (7Horowitz A. Simons M. J. Biol. Chem. 1998; 273: 10914-10918Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar) phosphorylation of Ser183 in the cytoplasmic tail of syndecan-4. The capacities of the cytoplasmic tail of syndecan-4 to undergo multimerization and to activate PKCα were manifest only in the presence of PIP2. A recent NMR study reported on PIP2 binding to a lysine-rich 9-amino acid-long variable region (LGKKPIYKK) from the middle of the cytoplasmic tail of syndecan-4 (8Lee D. Oh E.S. Woods A. Couchman J.R. Lee W. J. Biol. Chem. 1998; 273: 13022-13029Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). The interaction of PIP2 with this region could conceivably be mediated in part by electrostatic bonds between the two phosphates attached to the PIP2 inositol ring and the positively charged lysines of the variable region. This electrostatic interaction could be disrupted by the phosphorylation of Ser183 located 3 residues upstream of the variable region. An interaction of a similar nature may take place between PIP2 and several basic residues located in the N-terminal actin-binding domain of α-actinin (13Fukami K. Sawada N. Endo T. Takenawa T. J. Biol. Chem. 1996; 271: 2646-2650Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The specific binding of PIP2 to the pleckstrin homology domains of several proteins also appears to be mediated by an electrostatic interaction between the PIP2 phosphates and positively charged lysines in the pleckstrin homology domain (14Harlan J.E. Hajduk P.J. Yoon H.S. Fesik S.W. Nature. 1994; 371: 168-170Crossref PubMed Scopus (678) Google Scholar). Moreover, the syndecan-4 variable region resembles the consensus sequences for PIP2-binding motifs (15Yu F.X. Sun H.Q. Janmey P.A. Yin H.L. J. Biol. Chem. 1992; 267: 14616-14621Abstract Full Text PDF PubMed Google Scholar). A reduction in PIP2 binding following phosphorylation of serine residues, similar to the one we reported here, is thought to occur in a lysine-rich sequence of the myristoylated alanine-rich protein kinase C substrate (16Glaser M. Wanaski S. Buser C.A. Boguslavsky V. Rashidzada W. Morris A. Rebecchi M. Scarlata S.F. Runnels L.W. Prestwich G.D. Chen J. Aderem A. Ahn J. McLaughlin S. J. Biol. Chem. 1996; 271: 26187-26193Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). The mechanism of PKCα activation by the cytoplasmic tail of syndecan-4 is thought to require formation of cytoplasmic tail multimers (4Oh E.S. Woods A. Couchman J.R. J. Biol. Chem. 1997; 272: 11805-11811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Ser183 phosphorylation prevents this oligomerization by inhibiting PIP2 binding to the variable region of the syndecan-4 cytoplasmic tail. It follows, therefore, that the loss of PKCα activation by the cytoplasmic tail upon phosphorylation of Ser183 is a direct consequence of the concomitant reduction in affinity to PIP2 and impaired multimerization. Because the cytoplasmic tail of syndecan-4 did not activate PKCδ, this activation may be specific to PKCα. On the other hand, Ser183 phosphorylation had no effect on the capacity of the syndecan-4 cytoplasmic tail to bind PKCα. The ability of syndecan-4 to activate PKCα signaling in endothelial cells, the regulation of this signaling by syndecan-4 phosphorylation, and the previously demonstrated bFGF-dependent regulation of the state of syndecan-4 cytoplasmic tail phosphorylation suggests the existence of a novel bFGF-dependent signaling pathway. The same signaling pathway may also be employed by other events affecting syndecan-4 phosphorylation. We thank Drs. Lewis C. Cantley and Kiyotaka Nishikawa for helpful discussions and the Protein Chemistry Core Facility (which is supported by National Institutes of Health Grant P50 HL 56993) for providing recombinant PKCα and δ." @default.
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• W2080559953 title "Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα" @default.
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