Decorin Activates the Epidermal Growth Factor Receptor and Elevates Cytosolic Ca2+ in A431 Carcinoma Cells

Patel, Sandip; Santra, Manoranjan; McQuillan, David J.; Iozzo, Renato V.; Thomas, Andrew P.

doi:10.1074/jbc.273.6.3121

Cited by 121 publications

(49 citation statements)

References 24 publications

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“…In tumor cells overexpressing the EGF receptor, the MAPK pathway and calcium influx have been shown to be involved in decorin signaling (15,16). However, these pathways are not used in endothelial cells cultured on fibrillar collagen, i.e.…”

Section: Figmentioning

confidence: 99%

“…The relative quantification of gene expression by reverse transcription-polymerase chain reactions (RT-PCR) was validated as described (25) with minor modifications. cDNA synthesis was performed with Omniscript reverse transcriptase (Qiagen) and random primer (pd(N) 6 , Roche Diagnostics) and oligo(dT) 16 (MWG Biotech). cDNA (50 ng) was incubated with SYBR Green PCR buffer, nucleotides, AmpliTaq Gold DNA polymerase (PE Biosystems, Weiterstadt, Germany) and the primers for the different human genes listed in Table I (each 0.2 M, final concentration).…”

Section: Methodsmentioning

confidence: 99%

“…In squamous carcinoma cells it was shown that decorin as well as EGF can induce a calcium influx (16). To investigate whether an analogous situation can be found in EA.hy 926 cells, the cells were kept on collagen-coated coverslips for 24 h prior to decorin addition (100 g/ml).…”

Section: ј-Acctggtgctcagtgtagcc-3јmentioning

confidence: 99%

“…More recently it has been shown that decorin can also directly influence cell behavior. In A431 squamous carcinoma cells, decorin binds to the EGF receptor and increases its phosphorylation, thereby leading to an activation of the MAPK pathway, mobilization of calcium, and up-regulation of p21, an inhibitor of cyclin-dependent kinases (13)(14)(15)(16). The activation of the MAPK pathway finally leads to growth inhibition in that experimental system.…”

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confidence: 99%

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Decorin-mediated Signal Transduction in Endothelial Cells

Schönherr¹,

Levkau²,

Schaefer³

et al. 2001

Journal of Biological Chemistry

101

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Endothelial cells undergoing angiogenesis express decorin, a small multifunctional proteoglycan. We have shown that decorin is causally involved in the formation of capillary-like structures and a decrease in apoptosis in endothelial cells cultured in a collagen lattice. Here we investigate signal transduction pathways mediating the effects of decorin. Reverse transcription-polymerase chain reaction demonstrated that p21 and p27, two inhibitors of cyclin-dependent kinases, were up-regulated by decorin induction. Decorin also increased protein levels of p21 and caused its translocation into the nucleus. p21 synthesis started 6 h after decorin addition and reached a plateau after 18 h, while cyclin A, which was also induced, peaked at 12 h and declined below basal levels within 24 h. These effects were mediated by the Akt/protein kinase B pathway. Akt phosphorylation at Thr-308 increased 4-fold and at Ser-473 1.4-fold within 10 min after decorin addition. Overexpression of dominant negative Akt inhibited the decorin-mediated induction of p21 and cyclin A, but had no effect on p27. These results show that decorin is a signaling molecule in sprouting endothelial cells where it acts via different pathways, one of them involving Akt/protein kinase B.

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Section: Figmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ј-Acctggtgctcagtgtagcc-3јmentioning

confidence: 99%

mentioning

confidence: 99%

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Decorin-mediated Signal Transduction in Endothelial Cells

Schönherr¹,

Levkau²,

Schaefer³

et al. 2001

Journal of Biological Chemistry

101

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“…This interaction triggers a signal cascade leading to activation of mitogen activated protein kinases (29), mobilization of intracellular calcium (31), up-regulation of p21 WAF1/CIP1 (p21) (25,32), and ultimately to growth suppression (13,14,25). However, following a transient stimulation of the EGFR kinase, decorin causes a sustained down-regulation of the EGFR (33) and other ErbB members of receptor tyrosine kinase (34), an action that would negatively affect tumor growth.…”

mentioning

confidence: 99%

Decorin Binds to a Narrow Region of the Epidermal Growth Factor (EGF) Receptor, Partially Overlapping but Distinct from the EGF-binding Epitope

Santra¹,

Reed²,

Iozzo

2002

Journal of Biological Chemistry

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210

160

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Decorin, a small leucine-rich proteoglycan, is a key regulator of tumor growth by acting as an antagonist of the epidermal growth factor receptor (EGFR) tyrosine kinase. To search for cell surface receptors interacting with decorin, we generated a decorin/alkaline phosphatase chimeric protein and used it to screen a cDNA library by expression cloning. We identified two strongly reactive clones that encoded either the full-length EGFR or its ectodomain. A physiologically relevant interaction between decorin and EGFR was confirmed in the yeast two-hybrid system and further validated by experiments using EGF/EGFR interaction and transient cell transfection assays. Using a panel of deletion mutants, decorin binding was mapped to a narrow region of the EGFR within its ligand-binding L2 domain. Moreover, the central leucine-rich repeat 6 of decorin was required for interaction with the EGFR. Site-directed mutagenesis of the EGFR L2 domain showed that a cluster of residues, His 394 -Ile 402 , was essential for both decorin and EGF binding. In contrast, K465, previously shown to be cross-linked to epidermal growth factor (EGF), was required for EGF but not for decorin binding. Thus, decorin binds to a discrete region of the EGFR, partially overlapping with but distinct from the EGF-binding domain. These findings could lead to the generation of protein mimetics capable of suppressing EGFR function.Decorin, a prototype member of an expanding family of small leucine-rich proteoglycans (1), plays pivotal roles in modulating matrix assembly (2-5) and cell proliferation (6 -8). Most of the biological functions of decorin are mediated by the protein core's unique organization of 10 tandem leucine-rich repeats (LRR) 1 which fold into an arch-shaped structure (9) whose concave surface is well suited to bind both globular and nonglobular proteins (2, 10, 11) as well as metal ions (12). Decorin expression is markedly suppressed in most transformed cells derived from primary malignant tumors (13-15) or in cells transformed by oncogenes such as vSrc (16), vJun (17), and ATF3 (18). On the contrary, decorin expression is markedly up-regulated during quiescence (19,20), and its levels can reach ϳ40-fold in post-confluent fibroblasts (21). We have previously shown that decorin expression is enhanced around invasive carcinomas (22) and have proposed that decorin might represent a natural antagonist to the growing cancer cells (1). This working hypothesis is corroborated by the established effects of decorin on growth factor-mediated tumor progression (23, 4) and by its profound cytostatic effects on a wide variety of tumor cell lines (13,14,24,25). Lack of decorin is permissive for tumor development insofar as bitransgenic mice, lacking both decorin and the tumor suppressor p53, develop an accelerated lymphoma tumorigenesis (26). These earlier reports have been supported by the recent observation that decorin gene expression is differentially down-regulated in hepatocellular (27) and ovarian (28) carcinomas vis á vis their normal counter...

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Differential expression of decorin and biglycan genes during palatogenesis in normal and retinoic acid–treated mice

Zhang

Mori

Iseki

et al. 2003

Developmental Dynamics

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Proteoglycans are involved in secondary palate formation. In the present study, we focused on two small leucine-rich proteoglycans, decorin and biglycan, because they assembled extracellular matrix molecules such as collagens and modulated signaling pathway of transforming growth factor-␤. To investigate the functions of decorin and biglycan in palatogenesis, we compared their mRNA expression patterns between normal palate and retinoic acid-induced cleft palate in mice by using in situ hybridization analysis during the period of embryonic day 13.5 (E13.5) to E15.5. On E13.5, decorin mRNA was expressed in the epithelia and mesenchyme on the nasal side of the developing secondary palate. During the period the palate shelves were fusing (E14.5), decorin mRNA was strongly expressed in the mesenchyme but its expression pattern was asymmetric; decorin mRNA expression area in the nasal side was broader than that in the oral side. The expression of decorin mRNA was hardly detected in the mesenchyme on either side of the medial edge epithelium. After fusion (E15.5), its expression converged to the mesenchyme just around the palatine bone. Biglycan mRNA was ubiquitously distributed throughout the palatal mesenchyme for the mid-gestation period. Its expression area became limited to the ossification area within the palate after the late gestation period. In the retinoic acid-treated mice, the area of the decorin gene expression expanded to the core region of the palate primordium where little signal was observed in control mice. On the other hand, biglycan in the retinoic acid-treated mice did not show remarkable change in its distribution patterns compared with that in the control mice. These findings suggest that decorin and biglycan play distinct roles in palatogenesis, and decorin was more actively involved in the process of secondary palate formation than biglycan. Up-regulation of decorin gene expression in the retinoic acid-treated mice might influence the pathogenesis of cleft palate. Developmental Dynamics 226:618 -626, 2003.

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Decorin Activates the Epidermal Growth Factor Receptor and Elevates Cytosolic Ca2+ in A431 Carcinoma Cells

Cited by 121 publications

References 24 publications

Decorin-mediated Signal Transduction in Endothelial Cells

Decorin-mediated Signal Transduction in Endothelial Cells

Decorin Binds to a Narrow Region of the Epidermal Growth Factor (EGF) Receptor, Partially Overlapping but Distinct from the EGF-binding Epitope

Differential expression of decorin and biglycan genes during palatogenesis in normal and retinoic acid–treated mice

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