New Src-Family Kinase Activator

Abstract

Members of the Src familiy of protein kinases contribute to signals emanating from various receptors on the cell membrane, but the mechanisms by which the receptors modulate kinase activity is unclear. Members of the Src family show interactions between protein domains that are thought to control kinase activity. In fact, the SH3 (Src homology 3) domain binds to a linker region within the protein and this binding favors an inactive conformation of the kinase. However, the sequence that is bound is actually not an optimal SH3-binding motif, so other higher affinity SH3-binding targets can potentially compete for binding and relieve this inhibition. In fact, activation of the Src family member Lck by the receptors CD28 or CD2 appears to be mediated by binding of an SH3 ligand in the receptor to the SH3 domain of the kinase. Now Cen et al. have discovered a new activator of Src-like kinases, Unc119, that appears to work in a similar manner. Unc119 interacts with the interleukin 5 (IL-5) receptor in a two hybrid screen and in vivo in human eosinophils. Unc119 contains both SH2- and SH3-binding motifs and interacts with the tyrosine kinase Lyn through these domains. Such binding of Unc119 to Lyn increased kinase activity or the enzyme. IL-5 signals through Lyn to promote survival of eosinophils. Eosinophils that took up Unc119 that had been modified to contain nuclear localization signals and a retroviral gp41 fusion domain showed increased activity of Lyn and prolonged survival. On the contrary, when cells took up antibody to Unc119 in similar experiments, Il-5-induced survival was reduced. Thus, Unc119 may represent a new class of regulatory protein for Src family kinases. O. Cen, M. M. Gorska, S. J. Stafford, S. Sur, R. Alam, Identification of Unc119 as a novel activator of SCR-type tyrosine kinases. J. Biol. Chem. 278 , 8837-8845 (2003). [Abstract] [Full Text]