Biomedical subjects

A Horowitz

Publications and source records attributed to A Horowitz.

At least 19 recordsLinked to original sources

PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗

PubMed2006

Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes.

Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20-30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n=242) were divided into subgroups with high (n=127) and low (n=115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n=142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic cholinergic receptor genes. We found nominally significant (P<0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P<0.007-0.05) in CHRNB2 and nominal (P<0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the best-fitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P=5.9 x 10(-14), Nagelkerke r(2)=0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P=2.24 x 10(-7), Nagelkerke r(2)=0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic cholinergic receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.

Adult↗

PubMed2005

The spatial and temporal trends of Cd, Cu, Hg, Pb and Zn in Seine River floodplain deposits (1994-2000).

Fresh floodplain deposits (FD), from 11 key stations, covering the Seine mainstem and its major tributaries (Yonne, Marne and Oise Rivers), were sampled from 1994 to 2000. Background levels for Cd, Cu, Hg, Pb, and Zn were established using prehistoric FD and actual bed sediments collected in small forested sub-basins in the most upstream part of the basin. Throughout the Seine River Basin, FD contain elevated concentrations of Cd, Cu, Hg, Pb and Zn compared to local background values (by factors>twofold). In the Seine River Basin, trace element concentrations display substantial downstream increases as a result of increasing population densities, particularly from Greater Paris (10 million inhabitants), and reach their maxima at the river mouth (Poses). These elevated levels make the Seine one of the most heavily impacted rivers in the world. On the other hand, floodplain-associated trace element levels have declined over the past 7 years. This mirrors results from contemporaneous suspended sediment surveys at the river mouth for the 1984-1999 period. Most of these temporal declines appear to reflect reductions in industrial and domestic solid wastes discharged from the main Parisian sewage plant (Seine Aval).

Disasters↗

PubMed2005

Photolysis and OH-Initiated oxidation of glycolaldehyde under atmospheric conditions.

The photolysis and OH-initiated oxidation of glycolaldehyde (HOCH(2)CHO), which are relevant atmospheric processes, have been investigated under different conditions using complementary methods in three different laboratories. The UV absorption cross sections of glycolaldehyde determined in two of the laboratories are in excellent agreement. The photolysis of glycolaldehyde in air has been investigated in a quartz cell with sunlamps and in the EUPHORE chamber irradiated by sunlight. The mean photolysis rate measured under solar radiation was (1.1 +/- 0.3) x 10(-5) s(-1) corresponding to a mean effective photolysis quantum yield of (1.3 +/- 0.3). The major products detected were HCHO and CO, whereas CH(3)OH was also observed with an initial yield around 10%. Evidence for OH production was found in both experiments using either OH scavenger or OH tracer species. Photolysis of glycolaldehyde was used as the OH source to measure the reaction rate constants of OH with a series of dienes by the relative method and to identify and quantify the oxidation products of the OH-initiated oxidation of 2-propanol. The different experiments suggest that OH is produced by the primary channel: HOCH(2)CHO + hnu --> OH + CH(2)CHO (1). The rate constant of the OH reaction with glycolaldehyde has been measured at 298 K using the relative method: k(glyc) = (1.2 +/- 0.3) x 10(-11) cm(3) molecule(-1) s(-1). The product study of the OH-initiated oxidation of glycolaldehyde in air has been performed using both a FEP bag and the EUPHORE chamber. HCHO was observed to be the major product with a primary yield of around 65%. Glyoxal (CHOCHO) was also observed in EUPHORE with a primary yield of (22 +/- 6)%. This yield corresponds to the branching ratio ( approximately 20%) of the H-atom abstraction channel from the CH(2) group in the OH + HOCH(2)CHO reaction, the major channel ( approximately 80%) being the H-atom abstraction from the carbonyl group. The data obtained in this work, especially the first determination of the photolysis rate of glycolaldehyde under atmospheric conditions, indicate that the OH reaction and photolysis can compete as tropospheric sinks for glycolaldehyde. Since glycolaldehyde is a significant oxidation product of isoprene whereas the photolysis of glycolaldehyde is a significant source of methanol, isoprene might contribute a few percent of the global budget of methanol.

Journal Article↗

PubMed2005

The effect of rehabilitation on depression among visually disabled older adults.

There has been a great deal of interest in identifying the impact of rehabilitation on psychological well-being, as well as functional ability, among elders with disabilities, but empirical data remain limited. This descriptive study of participants in vision rehabilitation service examines the effect of specific vision rehabilitation services (low vision clinical services, skills training, counseling, optical device use, and adaptive device use) on change in depression among a sample of older adults with age-related vision impairments. Participants (N = 95) were interviewed at application for services and then approximately two years later. Findings from hierarchical regression analyses indicated that low vision clinical services, counseling, and use of optical devices, in separate models, each significantly contributed to a decline in depression, after controlling for age, health status, vision status, functional disability, as well as baseline depression. When all service variables were entered into the same equation, they explained an additional 10% of the variance in change in depression. Given the well documented robust relationship between disability and depression, findings point to the influence of vision rehabilitation interventions on both physical and psychological functioning, and underscore the need for future, controlled research on rehabilitation service models that address mental health issues.

Adaptation, Psychological↗

PubMed2003

Pregnancy outcome after laparoscopy or laparotomy in pregnancy.

STUDY OBJECTIVE: To assess obstetric performance and fetal outcomes after laparoscopy or laparotomy performed during pregnancy. DESIGN: Nationwide, multicenter, retrospective chart review (Canadian Task Force classification II-2). SETTING: Seventeen hospitals throughout Israel: 12 university or university-affiliated hospitals and 5 general hospitals. PATIENTS: Three hundred eighty-nine pregnant women. INTERVENTION: Laparoscopy or laparotomy for various indications. MEASUREMENTS AND MAIN RESULTS: Of 192 laparoscopies performed, 141 were during the first, 46 during the second, and 5 during the third trimester; respective figures for 197 laparotomies were 63, 110, and 24. No intraoperative complications were reported for either procedure. Six and 25 women had complications after laparoscopy and laparotomy, respectively. There was no significant difference in abortion rates between groups. Mean gestational age at delivery and mean birthweight were comparable between groups. No significant difference was found in frequency of fetal anomalies between groups or when compared with the Israel register of anomalies. CONCLUSION: Operative laparoscopy seems to be as safe as laparotomy in pregnancy.

Adult↗

PubMed2003

The influence of health, social support quality and rehabilitation on depression among disabled elders.

This study examined the influence of health, social support, disability, and vision rehabilitation services on depression among visually impaired older adults seeking vision rehabilitation services. Participants (n = 95) were interviewed at application and approximately two years later. The first hierarchical regression model focused on concurrent relationships at baseline. The second model used baseline health and social support variables, along with indicators of change in vision and use of rehabilitation services, in order to predict change in depression over time. Findings indicate that being unmarried, in poorer health, having lower quality of relationships with family, and lower stability in friendships were significant independent risk factors for initial depression, explaining 50% of the variance. Decline in depression over time was predicted by younger age, better self-rated health, stability of friendships, and use of rehabilitation services that, along with baseline depression, explained 61% of the variance in depressive symptomatology at the two-year follow-up. Findings highlight the importance of qualitative aspects of social support for older disabled adults, as well as the distinction that needs to be made between factors that predict concurrent mental health status and those predicting change in status over time.

Activities of Daily Living↗

PubMed2001

Syndecan-4-mediated signalling.

The paradigm of cell surface proteoglycan function has been centered on the role of the ectoplasmic heparan sulfate (HS) chains as acceptors of a wide array of ligands, including extracellular matrix (ECM) proteins and soluble growth factors. Within this picture, the core proteins were assigned only a passive role of carrying the glycosaminoglycan (GAG) chains without direct participation in mediating outside-in signals generated by the binding of the above ligands. It appears now, however, that, side by side with the integrins and the tyrosine kinase receptors, the core proteins of the syndecan family of transmembrane proteoglycans are involved in signaling. The highly conserved tails of all the four members of the syndecan family contain a carboxy-terminal PDZ (Postsynaptic density 95, Disk large, Zona occludens-1)-binding motif, capable of forming multimolecular complexes through the binding of PDZ adaptor proteins. The cytoplasmic tail of the ubiquitously expressed syndecan-4 is distinct from the other syndecans in its capacity to bind phosphatidylinositol 4,5-bisphosphate (PIP2) and to activate protein kinase C (PKC) alpha. These properties may confer on syndecan-4 specific and unique signaling functions.

Amino Acid Sequence↗

PubMed2001

The pharmacokinetics of the novel promotile drug, tegaserod, are similar in healthy subjects-male and female, elderly and young.

BACKGROUND: Tegaserod (HTF 919) is a selective 5-HT4 receptor partial agonist in development for the treatment of irritable bowel syndrome. AIM: This study aimed to assess the effect of age and gender on the single-dose pharmacokinetics of tegaserod. METHODS: In a parallel-group, open-label study, a single dose of tegaserod (12 mg) was administered to four groups of healthy young male, young female, elderly male and elderly female subjects (n=10 per group). Blood samples were collected from 0 to 24 h postdose. Non-compartmental pharmacokinetics evaluation and statistical analysis (ANOVA and Wilcoxon signed ranks test for tmax) were performed. RESULTS: Tegaserod was well tolerated in all groups. There was no effect of age or gender on tmax and Cmax. Gender did not affect AUC0-infinity and AUC0-tz; there was a statistically significant effect of age on these parameters. AUC0-infinity and AUC0-tz in the elderly were greater than in the young (AUC0-infinity ratio 1.37, P < 0.001; AUC0-tz ratio 1.23, P=0.029). This increase in exposure is judged not to be clinically relevant because it is within the variability in the pharmacokinetics parameters of tegaserod and because the dose-response relationship of tegaserod is relatively shallow. CONCLUSIONS: No dose adjustment for age or gender is recommended in tegaserod therapy.

Adolescent↗

PubMed2001

Immunohistochemical analysis of candidate gene product expression in the duodenal epithelium of children with coeliac sprue.

BACKGROUND: Coeliac sprue is a chronic disease, in which there is a characteristic mucosal lesion of the small intestine and impaired nutrient absorption, which improves upon the withdrawal of wheat gliadins and related grain proteins from the diet. Biopsy specimens demonstrate diffuse enteritis with pronounced atrophy or total loss of villi. There is also a long term risk of malignant disease. AIMS: To compare the immunoexpression of DCC (deleted in colon cancer), p53, E-cadherin, and beta-catenin in the duodenal mucosa of children with coeliac disease with that seen in children with no evidence of small intestinal disease. METHODS: To gain more insight into the genetic and immunohistochemical alterations of the duodenal epithelium in coeliac disease, 21 endoscopic biopsies from children with coeliac disease and 10 duodenal biopsies from children without coeliac disease were immunohistochemically evaluated for p53, DCC, E-cadherin, and beta-catenin. RESULTS: DCC expression was not reduced in patients with coeliac disease compared with those without coeliac disease. p53 positive nuclear immunostaining was seen in seven of the 21 patients with coeliac disease. Positive nuclear staining was seen mainly in the deep and the lateral aspects of the crypts. All patients in the control group were negative for p53. In nine and three of the 21 patients with coeliac disease, respectively, the immunohistochemical expression of E-cadherin and beta-catenin was reduced. However, both E-cadherin and beta-catenin immunostaining in the control group was not altered. CONCLUSIONS: E-cadherin and beta-catenin were reduced in the duodenal epithelium of children with coeliac disease when compared with normal mucosa. p53 was overexpressed in the duodenal mucosa of patients with coeliac disease. The reduced expression of E-cadherin and beta-catenin and p53 overexpression may contribute to the morphological changes seen in the small intestinal mucosa in coeliac disease.

Adolescent↗

PubMed2001

The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects.

Tegaserod (HTF 919) is a highly specific 5-HT4 receptor partial agonist that exhibits promotile activity throughout the gastrointestinal tract and is under development for the treatment of functional gastrointestinal motility disorders. The present study was designed to assess the effect of multiple doses of tegaserod on the single-dose pharmacokinetics and pharmacodynamics of digoxin, a commonly prescribed agent for congestive heart failure. The study was an open-label, randomized, two-period crossover design of 12 healthy subjects. One treatment included digoxin treatment alone; the other treatment included a combined digoxin and tegaserod treatment. On day 1 of the digoxin treatment period, subjects received a single 1 mg oral dose of digoxin. In the combined tegaserod/digoxin treatment period, subjects received a single oral dose of 1 mg digoxin after 3 days of tegaserod (6 mg bid). After coadministration of tegaserod, systemic exposure to digoxin was decreased; mean AUC decreased by 11.9% (p < 0.05) relative to digoxin alone. Cmax was decreased by about 15% (p < 0.05). The 0.5-hour difference in the median tmax between the two treatments was not statistically significant. Because the steady-state trough concentration of digoxin (C(SS,min)) correlates with pharmacological effects, C(SS,min) for digoxin alone and in combination with tegaserod was simulated based on both parametric compartmental modeling and nonparametric superpositioning approaches. The predicted arithmetic mean C(SS,min) for combination therapy is 86% to 89% of that following digoxin alone. Likewise, the predicted arithmetic mean steady-state peak concentration (C(SS,min)) and AUC at steady state during a dosing interval (AUC(SS,tau)) have a similar decrease. This extent of decrease in systemic exposure of digoxin at steady state is unlikely to be clinically relevant. Administration of tegaserod (6 mg bid) was well tolerated, both alone and in combination with a single dose of digoxin. There were no pharmacodynamic changes in ventricular rate and QT interval following coadministration of tegaserod with digoxin. The 1.5-hour and 2-hour postdose plasma concentrations of tegaserod on days 3 and 4 confirmed adequate exposure. In conclusion, dose adjustment for digoxin is unlikely to be needed when tegaserod is coadministered.

Adolescent↗

PubMed2001

Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus.

Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insulin secretion is hypothesized to be important in the deterioration of glucose tolerance. To determine whether enhancement of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insulinotropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secretion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 +/- 2.1 yr, x +/- SEM; body mass index 29.7 +/- 1.0 kg/m(2); fasting plasma glucose 8.1 +/- 0.1 mM). beta-Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide administration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide enhanced glucose-induced insulin release, compared with placebo (area under the curve -15-300 min: nateglinide 23,595 +/- 11,212 pM/min, glyburide 54,556 +/- 15,253 pM/min, placebo 10,242 +/- 2,414 pM/min). The profiles of insulin release demonstrated significant enhancement of release between -15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 +/- 0.04%/min), but it did not increase significantly with glyburide (0.79 +/- 0.04%/min), compared with placebo (0.76 +/- 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose concentration with glyburide (3.8 +/- 0.2 mM), compared with nateglinide (5.0 +/- 0.2 mM) and placebo (5.9 +/- 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the kinetics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further reduction in glucose levels and a lower nadir.

Aged↗

PubMed2001

The use of magnetic resonance imaging in the differential diagnosis between starch and fecal peritonitis.

Granulomatous peritonitis, caused by the starch from the surgeons' gloves, is a hypersensitivity reaction that can complicate abdominal surgery and mimic other causes of peritonitis. The diagnosis of this entity is difficult to make, and relies on a high index of suspicion. We suggest the use of magnetic resonance imaging to facilitate the diagnosis of this condition, based on an experimental animal model. 84 rats were subjected to laparotomy, and the abdominal cavity was exposed to either saline solution, talc solution, starch solution or fecal material by creating a cecal perforation. TI-weighted magnetic resonance images, with and without gadolinum enhancement, were taken after 3, 5 and 10 days. The animals were then sacrificed and the abdominal contents were evaluated both macroscopically and microscopically. Both talc and starch caused gross adhesions involving the entire abdominal viscera, and microscopy revealed signs of inflammation and fibrosis. Starch induced reactive granulomas. The adhesions in the cases of fecal peritonitis were confined to the area of the perforation. MR images of the starch peritonitis group was remarkable for a diffuse pathological process with enhancement of the omentum and the peritoneum after gadolinum injection. The MR readings of the fecal peritonitis group showed a localized process with no diffuse enhancement of the peritoneum. The striking differences between the magnetic resonance images of starch and fecal peritonitis in rats suggest that this modality is both sensitive and specific in diagnosing starch peritonitis in a rat model. Early non-invasive diagnosis of these separate entities would ease the establishment of the appropriate treatment. We are currently investigating the use of MRI imaging in suspected starch peritonitis in humans.

Animals↗

PubMed2000

Fatal haemorrhage following male ritual circumcision.

Lethal complications following ritual circumcision are extremely rare, the most common being sepsis. We present here a case of fatal haemorrhage from a tiny incision of the glans, following a 'home' circumcision of a 6-week-old baby. The post-mortem examination disclosed idiopathic neonatal hepatitis. It is suggested that the previously undiagnosed hepatic condition was responsible for the fatal haemorrhage.

Journal Article↗

PubMed2000

The amyloid deposit in calcifying epithelial odontogenic tumor is immunoreactive for cytokeratins.

Calcifying epithelial odontogenic tumor, also known as Pindborg tumor, is a rare benign tumor with locally aggressive behavior. It is characterized by squamous epithelial cells, calcifications, and eosinophilic deposits that have been identified as amyloid. We report a case of calcifying epithelial odontogenic tumor and investigate the nature of the amyloid, using histologic, immunohistochemical, and ultrastructural studies. The amyloid was immunohistochemically negative for basement membrane components and positive for all cytokeratin stains performed (cocktail of cytokeratins 1, 5, 6, 8, 13, and 16, and cytokeratins AE1 and AE3). The amyloid stained focally in a glandular-like pattern, reminiscent of the epithelial glandlike structures of the tumor. We conclude that the amyloid is derived from filamentous degeneration of keratin filaments that originate from the tumor squamous epithelium. The keratin degeneration is part of a developmental or aging process that the tumor undergoes.

Amyloid↗

PubMed1999

Phosphatidylinositol-4,5-bisphosphate mediates the interaction of syndecan-4 with protein kinase C.

Recent studies have demonstrated that the cytoplasmic tail of syndecan-4, a widely expressed transmembrane proteoglycan, can activate protein kinase Calpha in vitro, in combination with phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)). Syndecan-4 is involved in growth factor binding as well as in adhesion to extracellular matrix proteins, while PI-4,5-P(2) synthesis is modulated by growth factor and adhesion-generated signaling. The cooperative activation of PKCalpha by the proteoglycan and the phosphatidylinositol may constitute, therefore, an essential part of the cell's response to these extracellular signals. To characterize the activation mechanism of PKCalpha, we addressed here the nature of the interplay between syndecan-4, PI-4,5-P(2), and PKCalpha by measuring their mutual binding affinities and the specificity of their interactions. We found that the cytoplasmic tail of syndecan-4 is unlikely to bind directly to PKCalpha, and that this interaction critically depends on PI-4,5-P(2). The PI-4,5-P(2) specificity of the activation of PKCalpha is conferred by the cytoplasmic tail of syndecan-4, which has higher binding affinity for this phosphatidylinositol over phosphatidylinositol-3,4-bisphosphate and the -3,4,5-trisphospate. The activation is specific to PKCalpha and does not encompass the novel protein kinase C delta isoenzyme.

Binding Sites↗

PubMed1999

Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models.

We investigated the pharmacokinetics and therapeutic efficacy of cisplatin encapsulated in polyethyleneglycol-coated long-circulating liposomes in a formulation referred to as SPI-077, in three mouse tumor models (M-109 lung carcinoma inoculated s.c., J-6456 lymphoma inoculated i.p. and A-375 melanoma inoculated s.c.). Tumor-bearing mice were injected i.v. with single doses of SPI-077 and cisplatin. For pharmacokinetic experiments, mice were sacrificed at different timepoints post-treatment. Platinum levels were determined in plasma, spleen, liver, kidneys and tumors using flameless atomic absorption spectrophotometry. Survival times and/or tumor size were recorded for therapeutic studies. The pharmacokinetic studies revealed a prolonged circulation time and enhanced tumor uptake for SPI-077. In contrast to these results, no superior antitumor activity of SPI-077 over cisplatin could be observed in all tumor models. In vitro release experiments showed a negligible release (below 10%) of platinum from the liposomes. An in vitro cytotoxicity assay indicated a reduced cytotoxic activity of SPI-077 in comparison to cisplatin. We concluded that SPI-077 is being delivered to the tumor sites in a low bioavailability form, with extremely slow release kinetics. This explains the discrepant results of high platinum concentrations in tumors and reduced therapeutic activity after administration of SPI-077.

Animals↗

PubMed1998

Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase Calpha.

Syndecans are transmembrane proteoglycans capable of carrying both heparan and chondroitin sulfate chains. The cytoplasmic tail of syndecan-4 was recently reported to undergo in 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 Calpha (PKCalpha), 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 PKCalpha, 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, Ser183 phosphorylation abolished PIP2-dependent oligomerization of syndecan-4 cytoplasmic tails. We conclude that Ser183 phosphorylation regulates syndecan-4-dependent activation of PKCalpha 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.

Animals↗