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Identification of UNC119 as a novel activator of SRC-type tyrosine kinases
Osman Cen1, Magdalena M Gorska, Susan J Stafford
1Division of Allergy and Immunology, NIAID, National Institutes of Health Asthma and Allergic Diseases Research Center, Bethesda, Maryland 20892, USA.
Abstract:
Lyn, an Src-type tyrosine kinase, is associated with the interleukin (IL)-5 receptor in eosinophils. The mechanism of its activation is unknown. Through yeast two-hybrid screening we have cloned and characterized a new signaling molecule, Unc119, that associates with IL-5Ralpha and Src family tyrosine kinases. Unc119 induces the catalytic activity of these kinases through interaction with Src homology 2 and 3 domains. IL-5 stimulation of eosinophils increases Unc119 association with Lyn and induces its catalytic activity. Lyn is important for eosinophil survival. Eosinophils that are transduced with Unc119 have increased Lyn activity and demonstrate prolonged survival in the absence of IL-5. Inhibition of Unc119 down-regulates eosinophil survival. To our knowledge Unc119 is the first receptor-associated activator of Src family tyrosine kinases.
Insights
A novel protein, Unc119, activates Lyn tyrosine kinase, crucial for eosinophil survival. This discovery reveals a new mechanism for regulating Src family kinases in immune cells.
Area of Science:
- Immunology
- Cell Signaling
- Biochemistry
Background:
- Lyn, an Src-type tyrosine kinase, is linked to the interleukin-5 (IL-5) receptor in eosinophils, but its activation mechanism remains unclear.
- Src family tyrosine kinases play critical roles in cellular processes, including immune cell function and survival.
Purpose of the Study:
- To identify and characterize novel signaling molecules involved in Lyn kinase activation within eosinophils.
- To elucidate the mechanism by which Unc119 interacts with and activates Src family kinases, specifically Lyn.
Main Methods:
- Yeast two-hybrid screening was employed to identify interacting partners of the IL-5 receptor alpha subunit and Src family kinases.
- Biochemical assays were used to assess the catalytic activity of Lyn kinase upon interaction with Unc119.
- Eosinophil transduction with Unc119 and subsequent survival assays were performed to evaluate its functional role.
Main Results:
- A new signaling molecule, Unc119, was identified and characterized for its association with IL-5Ralpha and Src family kinases.
- Unc119 was shown to induce catalytic activity in Lyn kinase through interactions with its Src homology 2 and 3 domains.
- IL-5 stimulation enhanced Unc119-Lyn association and Lyn activity, leading to prolonged eosinophil survival, even without IL-5.
Conclusions:
- Unc119 is identified as the first known receptor-associated activator of Src family tyrosine kinases.
- Unc119 plays a significant role in eosinophil survival by modulating Lyn kinase activity.
- This finding provides a new mechanistic insight into the regulation of immune cell signaling and survival pathways.