Activation of Downstream Signals by the Long Form of the Leptin Receptor*

By Alexander S. Banks, Sarah M. Davis, S. Bates, M. G. Myers. Journal of Biological Chemistry, 2000

816 citations recorded by the source corpus.

The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr985 controls the tyrosine phosphorylation of SHP-2, and Tyr1138 controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr985-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr985 and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr1138-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr985 positively regulates the ERK → c-fospathway, and STAT3 binding to Tyr1138 mediates the inhibitory SOCS3 pathway.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/731254dd666782355e7c5c277f359dbeefceec94

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrine and Autonomic Systems

1. G. Frühbeck
2. M. Myers
3. J. Oakhill
4. M. Schwartz
5. S. Galic
6. G. Steinberg
7. K. Frayn
8. P. Trayhurn

In Epidemiology

1. B. Spiegelman
2. M. Myers
3. J. Oakhill
4. M. Schwartz
5. G. Frühbeck
6. S. Galic
7. G. Steinberg
8. E. Rosen

In Nutrition and Dietetics

1. G. Frühbeck
2. M. Myers
3. M. Schwartz

Citations in the corpus

• Molecular mechanisms of cancer development in obesity (2011, background): “Leptin signals through a transmembrane receptor (OBR) that contains intracellular tyrosines, which mediate downstream signalling via the ERK and STAT3 pathway”
• Intracellular signalling pathways activated by leptin. (2006, background): “Initial work showed that Tyr 985 of OB-Rb and homologous sites on related receptors represents a high-affinity binding site for SOCS3 during signalling by IL-6 receptor family members and that this site is critical for signalling inhibition by SOCS3 [98,101,102,111,113].”
• The weight of leptin in immunity (2004, background): “The expression of OBRb by T and B cells is of interest as it indicates a possible role for leptin in immune-cell activation and signal transduction, and might unveil new effects of leptin on as-yet-unexplored immune-cell function”
• Adipose tissue as an endocrine organ. (2010, background): “Likeother class I cytokine receptors,Ob-R lacks intrinsic tyrosine inase activity and therefore requires recruitment of the activated eceptor-associated kinases of the Janus family (JAKs) (Banks et al., 000). Activated signal transducers and activators of transcription STATs) then dimerize and trans”
• The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. (2001, background): “Only the fulllength isoform, the OB-Rb, is believed to be involved in leptin signaling and is considered to be the functional receptor.”
• STAT3 signalling is required for leptin regulation of energy balance but not reproduction (2003, background): “Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin actio”
• Mechanisms of leptin action and leptin resistance. (2008, background): “The activated Jak2 molecule then phosphorylates other tyrosine residues within the LRb/Jak2 complex to mediate downstream signaling (54, 55).”