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Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
J E Darnell1, I M Kerr, G R Stark
1Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021.
Abstract:
Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
Insights
Researchers uncovered a new signaling pathway where interferon-receptor interactions activate Jak kinases, which then enable signal transducers and activators of transcription (STATs) to regulate gene expression in the nucleus.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Immunology
Background:
- Interferon signaling is crucial for cellular responses to pathogens.
- The precise mechanisms of interferon signal transduction to the nucleus were not fully elucidated.
Purpose of the Study:
- To investigate the direct signal transduction pathway activated by interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma).
- To identify the key molecular players involved in transmitting interferon signals to the nucleus.
Main Methods:
- Studied transcriptional activation in response to IFN-alpha and IFN-gamma.
- Investigated the roles of Jak kinases and STAT proteins in the signaling cascade.
Main Results:
- A direct signal transduction pathway from the cell surface receptor to the nucleus was identified.
- Interferon-receptor interaction activates Jak kinases, which phosphorylate STAT proteins.
- Phosphorylated STATs translocate to the nucleus, bind DNA, and initiate transcription.
- Discovered multiple STAT family members and their involvement in signaling pathways initiated by other ligands.
Conclusions:
- The Jak-STAT pathway is a critical mechanism for interferon signal transduction.
- This pathway is conserved and utilized by various polypeptide ligands.
- Understanding this pathway opens avenues for therapeutic interventions targeting cytokine signaling.