Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase β/ζ signaling pathway: An alternative mechanism of receptor tyrosine kinase activation

Pablo Perez-Pinera, Wei Zhang, Yunchao Chang, Jose Antonio Vega, Thomas F. Deuel

Research output: Contribution to journalArticlepeer-review

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the constitutively active nucleophosmin-ALK oncoprotein in anaplastic large cell lymphomas (ALCL). Full-length ALK has a critical role in normal development and differentiation. Activated full-length ALK also is found in different malignant cancers. Nevertheless, the ligand to activate ALK remained unknown until recently, when ALK was proposed to be the physiological receptor of the cytokine pleiotrophin (PTN, Ptn). However, earlier studies had demonstrated that receptor protein tyrosine phosphatase (RPTP) β/ζ is a physiological PTN receptor. We now demonstrate that phosphorylation ofALKin PTN-stimulated cells is mediated through the PTN/RPTPβ/ζ signaling pathway. ALK is phosphorylated independently of a direct interaction of PTN with ALK. The data thus support a unique model of ALK activation. In cells not stimulated by PTN, RPTPβ/ζ dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTPβ/ζ is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTPβ/ζ; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTPβ/ζ signaling pathway is a critical regulator of the steady state levels of tyrosine phosphorylation and activation of ALK; the data support the conclusion that ALK phosphorylation and activation in PTN-stimulated cells are increased through a unique "alternative mechanism of RTK activation."

Original languageEnglish (US)
Pages (from-to)28683-28690
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number39
DOIs
StatePublished - Sep 28 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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