Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta.

Andres, Janet L.; Stanley, Krista; Cheifetz, Sela; Massagué, Joan

doi:10.1083/jcb.109.6.3137

Cited by 324 publications

(162 citation statements)

References 35 publications

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“…As previously noted, low expression levels of either OB-R⌬868 and OB-RY1141F generate a small enhancement of signaling for full-length OB-R and the OB-R/G-CSFR chimera. We speculate that this effect is attributable to either ligand presentation (37)(38)(39) or ligand passing as has previously been observed for the tumor necrosis factor receptor (40).…”

Section: Discussionmentioning

confidence: 82%

Leptin Receptor (OB-R) Signaling

White

Kuropatwinski

Devos

et al. 1997

Journal of Biological Chemistry

261

101

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The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the pretence of excess naturally occurring short form of OB-R.Leptin (OB) is an adipose tissue-derived secreted hormone that is thought to suppress appetite by regulating activities of satiety centers in the brain (1). The weight reducing effects of leptin appear to be mediated by interaction with the leptin receptor (OB-R) 1 in the hypothalamus, a region of the brain implicated in the control of body weight (2-4). In mice, mutations in the genes encoding either OB-R (db) or leptin (ob) result in profound early-onset obesity (5, 6). Multiple splice variants of OB-R mRNAs encoding proteins with different length intracellular domains have been detected (7,8). The mutant allele (db) of the OB-R gene was shown to encode a receptor with a truncated cytoplasmic domain (7,8), and more recent data suggest this receptor is signaling inactive (9). Thus, mounting evidence suggests the ability of leptin to regulate body weight is facilitated by downstream signaling events initiated by ligand-induced OB-R activation.Sequence homology and more recent functional data suggest OB-R is a member of the class I cytokine receptor superfamily (4, 10, 11). Receptors of this class lack intrinsic tyrosine kinase activity and are activated by ligand-induced receptor homo-or hetero-dimerization and in many cases require activation of receptor-associated kinases of the Janus family (JAKs) (12). JAKs associate with the membrane-proximal domain of the intracellular part of the cytokine receptors and serve to initiate signal transduction pathways following ligand-induced receptor activation. Included among the downstream targets of the JAK proteins are members of the STAT (Signal Transducers and Activators of Transcription) family of transcription factors (12). The STATs are DNA binding transcription factors that contain Src homology (SH2) domains that interact with receptor molecules through phosphorylated tyrosine residues. STAT proteins are activated by tyrosine phosphorylation...

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Section: Discussionmentioning

confidence: 82%

Leptin Receptor (OB-R) Signaling

White

Kuropatwinski

Devos

et al. 1997

Journal of Biological Chemistry

261

101

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“…Strong experimental evidence supports the concept that growth factors stored in the extracellular matrix and released in the course of its degradation are major mediators of such inductive processes. Numerous growth factors including fibroblast growth factor, platelet-derived growth factor, granulocyte/macrophage colony-stimulating factor, transforming growth factor-␤, and leukemia inhibitory factor have been shown to be associated with the extracellular matrix (21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

The Carboxyl-terminal Domain(111–165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency

Keyt¹,

Berleau²,

Nguyen³

et al. 1996

Journal of Biological Chemistry

553

452

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“…The ability of the extracellular matrix to function as a slow release reservoir for growth factors, as has been shown for bFGF, may explain how a molecule released over a short period of time can stimulate processes, such as angiogenesis, that take days or weeks (Flaumenhaft et al, 1989). Sim-ilarly, the binding of TGF-1l to the heparan and chondroitin sulfate proteoglycan, betaglycan, may concentrate TGF-f at the cell surface for presentation to high affinity receptors or aid in the clearance of TGF-3 (Andres et al, 1989). The potential importance of compartmentilization of growth factor activity via interaction with matrix has also been suggested for growth factors involved in bone maintenance (Hauschka et al, 1988), hematopoiesis (Gordon et al, 1988;Roberts et al, 1988), and lymphopoiesis (Kimura et al, 1991).…”

Section: Extracellular Matrixmentioning

confidence: 99%