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SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte
S J Cohney1, D Sanden, N A Cacalano
1DNAX Research Institute, Palo Alto, California 94304, USA.
Abstract:
Members of the recently discovered SOCS/CIS/SSI family have been proposed as regulators of cytokine signaling, and while targets and mechanisms have been suggested for some family members, the precise role of these proteins remains to be defined. To date no SOCS proteins have been specifically implicated in interleukin-2 (IL-2) signaling in T cells. Here we report SOCS-3 expression in response to IL-2 in both T-cell lines and human peripheral blood lymphocytes. SOCS-3 protein was detectable as early as 30 min following IL-2 stimulation, while CIS was seen only at low levels after 2 h. Unlike CIS, SOCS-3 was rapidly tyrosine phosphorylated in response to IL-2. Tyrosine phosphorylation of SOCS-3 was observed upon coexpression with Jak1 and Jak2 but only weakly with Jak3. In these experiments, SOCS-3 associated with Jak1 and inhibited Jak1 phosphorylation, and this inhibition was markedly enhanced by the presence of IL-2 receptor beta chain (IL-2Rbeta). Moreover, following IL-2 stimulation of T cells, SOCS-3 was able to interact with the IL-2 receptor complex, and in particular tyrosine phosphorylated Jak1 and IL-2Rbeta. Additionally, in lymphocytes expressing SOCS-3 but not CIS, IL-2-induced tyrosine phosphorylation of STAT5b was markedly reduced, while there was only a weak effect on IL-3-mediated STAT5b tyrosine phosphorylation. Finally, proliferation induced by both IL-2- and IL-3 was significantly inhibited in the presence of SOCS-3. The findings suggest that when SOCS-3 is rapidly induced by IL-2 in T cells, it acts to inhibit IL-2 responses in a classical negative feedback loop.
Insights
Suppressor of Cytokine Signaling-3 (SOCS-3) protein inhibits interleukin-2 (IL-2) signaling in T cells. Rapidly induced by IL-2, SOCS-3 acts as a negative feedback regulator, reducing T cell proliferation and STAT5b phosphorylation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- The SOCS/CIS/SSI protein family regulates cytokine signaling, but their specific roles, particularly in T cell interleukin-2 (IL-2) pathways, are not fully defined.
- No SOCS proteins have been previously linked to IL-2 signaling in T cells.
Purpose of the Study:
- To investigate the role of SOCS-3 in IL-2 signaling within T cells.
- To elucidate the mechanism by which SOCS-3 influences IL-2 response pathways.
Main Methods:
- Assessed SOCS-3 and CIS expression in response to IL-2 stimulation in T cell lines and human lymphocytes.
- Examined IL-2-induced tyrosine phosphorylation of SOCS-3 and its interaction with JAK kinases and the IL-2 receptor beta chain (IL-2Rbeta).
- Evaluated the impact of SOCS-3 on STAT5b phosphorylation and T cell proliferation in response to IL-2 and IL-3.
Main Results:
- SOCS-3 expression was rapidly induced by IL-2 in T cells, unlike CIS.
- SOCS-3 underwent tyrosine phosphorylation and associated with Jak1, inhibiting its phosphorylation, an effect enhanced by IL-2Rbeta.
- SOCS-3 interacted with the IL-2 receptor complex, reduced IL-2-induced STAT5b phosphorylation, and inhibited IL-2 and IL-3-mediated T cell proliferation.
Conclusions:
- SOCS-3 is rapidly induced by IL-2 in T cells and functions as a negative feedback regulator of IL-2 signaling.
- SOCS-3 inhibits IL-2 responses by interfering with JAK-STAT pathway components and receptor interactions.
- These findings define a critical role for SOCS-3 in modulating T cell responses to IL-2.