A complex interaction pattern of CIS and SOCS2 with the leptin receptor
Delphine Lavens1, Tony Montoye, Julie Piessevaux
1Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Interuniversity Institute for Biotechnology, VIB09, Ghent University, Belgium.
Journal of Cell Science
|May 11, 2006
Summary
Cytokine-inducible SH2 protein (CIS) and SOCS2 interact with the leptin receptor, influencing weight regulation. SOCS2 unexpectedly interferes with CIS binding, modulating leptin signaling pathways.
Area of Science:
- Endocrinology
- Molecular Biology
- Signal Transduction
Background:
- Leptin receptor signaling in the hypothalamus is crucial for regulating body weight, fat storage, and energy expenditure.
- Leptin also impacts peripheral functions like immunity, bone formation, and reproduction.
- Suppressor of cytokine signalling 3 (SOCS3) is known to play a role in leptin physiology.
Purpose of the Study:
- To investigate the interaction of cytokine-inducible SH2 protein (CIS) and SOCS2 with the leptin receptor.
- To elucidate the mechanisms by which CIS and SOCS2 modulate leptin receptor signaling.
- To identify specific motifs and binding affinities involved in these interactions.
Main Methods:
- Utilized MAPPIT (mammalian protein-protein interaction trap), a cell-based two-hybrid system.
- Investigated interactions between leptin receptor cytosolic domain motifs (Y985, Y1077) and CIS/SOCS2.
- Assessed interference of CIS and STAT5a prey recruitment and the role of SOCS2-CIS binding.
Main Results:
- CIS specifically binds to Y985 and Y1077 motifs of the leptin receptor.
- SOCS2 binds to Y1077 with higher affinity, interfering with CIS and STAT5a recruitment.
- SOCS2 also inhibits CIS binding at Y985 by directly binding to the CIS SOCS box, requiring elongin B/C for activity.
Conclusions:
- CIS and SOCS2 are novel interacting partners of the leptin receptor, expanding the understanding of leptin signaling regulation.
- SOCS2 exhibits a unique inhibitory mechanism, interfering with CIS binding to the leptin receptor through direct SOCS box interaction.
- These findings reveal complex regulatory crosstalk involving SOCS proteins in leptin-mediated physiological processes.
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