A Short Form of Leptin Receptor Performs Signal Transduction

Murakami, Takashi; Yamashita, Tatsuya; Iida, Mitsuru; Kuwajima, Masamichi; Shima, Kenji

doi:10.1006/bbrc.1996.6030

Cited by 185 publications

(108 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There were 4-fold more total leptin binding sites in cells transfected with HLR-5 than in cells transfected with other receptor isoforms. In agreement with previous studies, HLR-5 had the highest cell surface binding (18,28), while HLR-274 and HLR-15 had 5-fold fewer surface receptors, and HLR-67 showed very little surface binding of leptin. However, there were large intracellular pools of all the receptor isoforms.…”

Section: Resultssupporting

confidence: 92%

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Barr¹,

Lane²,

Taylor³

1999

Journal of Biological Chemistry

125

View full text Add to dashboard Cite

There are four known isoforms of the human leptin receptor (HLR) with different C-terminal cytoplasmic domains (designated by the number of unique C-terminal amino acids). In cells expressing HLR-5, -15, or -274, 15-25% of the leptin binding sites were located at the plasma membrane. In contrast, in cells expressing HLR-67, only 5% of the total binding sites were at the plasma membrane. Immunofluorescent microscopy showed that all four isoforms partially co-localized with calnexin and ␤-COP, markers of the endoplasmic reticulum and the Golgi, respectively. All isoforms were also detected in an unidentified punctate compartment. All isoforms were internalized via clathrin-mediated endocytosis, but at different rates. After 20 min at 37°C, 45% of a bound cohort of labeled ligand had been internalized by HLR-15, 30% by HLR-67, 25% by HLR-274, and 15% by HLR-5. Degradation of internalized leptin occurred in lysosomes. Overnight exposure to leptin down-regulated all isoforms, but to a variable extent. HLR-274 displayed the greatest down-regulation and also appeared to reach lysosomes more quickly than the other isoforms. The faster degradation of HLR-274 may help to terminate leptin signaling.Leptin is a peptide secreted primarily by adipose cells that regulates appetite, energy metabolism, and neuroendocrine function. Leptin acts both centrally, presumably in the hypothalamus, and directly on peripheral tissues (1-3). Leptin binding activates its receptor, a member of the cytokine receptor superfamily, which includes receptors for interleukins, prolactin, growth hormone, and erythropoietin (4, 5). As a result of differential mRNA splicing, there are several isoforms of the leptin receptor with different lengths and C-terminal sequences. The regions that are identical in all the receptor isoforms include the extracellular ligand binding domain, the transmembrane domain, and the first 29 amino acids in the cytoplasmic domain. (4, 6 -11).Some cytokine receptors (e.g. receptors for growth hormone, erythropoietin, and prolactin) form homodimers when activated by ligand, while others form hetero-oligomers (12)(13)(14). Recent studies have shown that leptin receptors form homodimers, both in the presence and absence of ligand (15, 16). Each leptin receptor binds one molecule of leptin, resulting in a tetrameric complex composed of two receptors and two leptin molecules. However, activation of the receptor is thought to result from a ligand induced conformational change rather than dimerization of the receptor (15, 17). All the leptin receptor isoforms contain a "box 1" Janus kinase binding site in the cytoplasmic domain. The longest form also contains a "box 2" motif and putative STAT 1 binding sites (5, 10, 11, 18) and thus only the long form is able to activate STAT proteins (18 -20).Receptor-mediated endocytosis is a well characterized mechanism for selectively transporting nutrients, hormones, and growth factors into cells. Often receptors are concentrated in clathrin-coated pits and then internalized in clathrin-coate...

show abstract

Section: Resultssupporting

confidence: 92%

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Barr¹,

Lane²,

Taylor³

1999

Journal of Biological Chemistry

125

View full text Add to dashboard Cite

show abstract

“…Since Morash et al (2000) reported that C6 glioma cells do not express long form of leptin receptor (ObRl), all the signal transduction observed in this study is due to the activation of short form of leptin receptor (ObRt). These results indicate that other than the role in leptin transporter, short form of leptin receptor also plays a notable role in mediating signal transduction (Bjorbaek et al 1997;Murakami et al 1997).…”

Section: Discussionmentioning

confidence: 98%

Leptin induces migration and invasion of glioma cells through MMP‐13 production

Yeh

Lee

et al. 2008

Glia

View full text Add to dashboard Cite

Leptin, the product of the obses gene, plays an important role in the regulation of body weight by coordinating metabolism, feeding behavior, energy balance and neuroendocrine responses. However, central regulation of leptin gene expression is different from that in the adipocytes. In addition, leptin has been found in many tumor cell lines and has been shown to have mitogenic and angiogenic activity in a number of cell types. Glioma is the most common primary adult brain tumor with poor prognosis due to the spreading of tumor cell to the other regions of brain easily. Here we found that malignant C6 glioma cells expressed more leptin and leptin receptors than non-malignant astrocytes. Furthermore, it was found that exogenous application of leptin enhanced the migration and invasion of C6 glioma cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) but not of MMP-2 and MMP-9 was increased in response to leptin stimulation. The leptin-induced increase of cell migration and invasion was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. The up-regulation of MMP-13 induced by leptin was mainly through p38 MAP kinase and NF-κB pathway. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-13 and leptin. Taken together, these results indicate that leptin enhanced migration and invasion of C6 glioma cells through the increase of 2

show abstract

“…46 The extended intracellular domain in the distal part of OB-Rb is required for the induction of STAT signaling. 47 Leptin has been shown to activate various isoforms of STATs, including STAT1, STAT3, STAT5 and STAT6, in a variety of cell types. 18,48 Among the various STAT proteins activated by OB-Rb, STAT3 has been shown to mediate the leptin signal in activated macrophages and in promoting the survival and activation of lymphocytes and peripheral blood mononuclear cells (PBMCs).…”

Section: Leptin and Autoimmunity M Vadacca Et Al 204mentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

View full text Add to dashboard Cite

Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

show abstract

A Short Form of Leptin Receptor Performs Signal Transduction

Cited by 185 publications

References 39 publications

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Leptin induces migration and invasion of glioma cells through MMP‐13 production

Leptin in immuno-rheumatological diseases

Contact Info

Product

Resources

About