Chapter 59 - Protein Tyrosine Kinase Receptor Signaling Overview

Abstract

This chapter reviews the general principles for protein tyrosine kinase (PTK) receptor structure, activation mechanism, and regulation. Each receptor consists of an extracellular ligand binding part, a single transmembrane domain, and an intracellular part with an intrinsic kinase domain. Protein tyrosine kinase receptors are generally activated by ligand-induced dimerization. This brings the receptor kinase domains close to each other, which results in autophosphorylation in trans within the intracellular parts of the receptors. The autophosphorylation occurs on tyrosine residues located within or outside the kinase domain of the receptor. Ligand-induced PTK receptor dimerization leads to autophosphorylation of the receptors in trans within the complex. The autophosphorylation serves two important roles such as it causes activation of the kinase domain, and it creates docking sites for downstream SH2- and PTP-domain-containing signaling molecules. Autophosphorylation may lead to activation of the kinase via several different mechanisms, of which more than one may apply for individual PTK receptors. Tyrosine residues exist within the activation loops of kinases, and after phosphorylation, these residues cause the loop to swing out and open up the active site of the kinase. Signaling via PTK receptors is also modulated by interaction with molecules recognizing other epitopes than phosphorylated tyrosines such as PDZ domain protein NHERF that binds to the C-terminal tail of the PDGF receptors, and the adaptor molecule Alix, which also binds to the PDGF β-receptor in a non-phosphorylation-dependent manner. The phosphorylation events performed by PTK receptors are counteracted by dephosphorylation by specific tyrosine phosphatases.