ABSTRACT
The ligands of mammalian receptor tyrosine kinases are hormones such as insulin and a large and heterogeneous family of growth factors. Phospho-acceptor tyrosine (Tyr) residues, insulin receptor substrates have many serine and threonine residues that are phosphorylated by a wide variety of protein kinases, resulting mostly in inhibition of signal transduction. Termination of T-cell receptor signaling follows the route that is typical for Tyr kinase-coupled receptors: Tyr-specific protein phosphatases cooperate with the E3 ubiquitin ligase Cbl in inactivating and degrading the tyrosine-phosphorylated components of the receptor complex. The oncogenic effect results from a continuous overactivation of mitogenic and anti-apoptotic signaling pathways stimulated by Tyr kinases and Tyr kinase-coupled receptors that are rescued from degradation. ITAM phosphorylation is catalyzed by the lymphocyte-specific Tyr kinase light-chain kinase, a member of the Src subfamily. Ephrin receptors constitute the largest subfamily of Tyr kinase-coupled receptors.
