Anaplastic lymphoma kinase: “Ligand Independent Activation” mediated by the PTN/RPTPβ/ζ signaling pathway

Anaplastic lymphoma kinase is essential in early development, differentiation, and maintenance of cell survival; nevertheless, the mechanism to activate ALK has remained elusive. ALK has remained an “Orphan Receptor.” The studies cited below describe a unique mechanism termed “Ligand Independent Activation.” It is shown that activation of ALK results when the cytokine pleiotrophin (PTN) interacts with its receptor, the receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ). Pleiotrophin inactivates the catalytic activity of RPTPβ/ζ, which, when not inactivated, dephosphorylates phosphotyrosine sites in the activation domain of ALK; as a consequence of the inactivation of RPTPβ/ζ by PTN, autophosphorylation and autoactivation of ALK rapidly follow. The PTN/RPTPβ/ζ signaling pathway thus regulates the catalytic activity of ALK and tyrosine phosphorylation levels of ALK downstream target proteins. Furthermore, since ALK is only one of the key ALK phosphoproteins targeted by the PTN/RPTPβ/ζ signaling pathway, the PTN/RPTPβ/ζ signaling pathway has the potential to coordinately regulate tyrosine phosphorylation of other different key proteins in multiple cellular compartments. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.