Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation.
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) beta/zeta is a physiological PTN receptor. We now demonstrate that phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTPbeta/zeta 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, RPTPbeta/zeta dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTPbeta/zeta is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTPbeta/zeta; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTPbeta/zeta 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."
Perez-Pinera
Pablo
P
Scripps Research Institute, La Jolla, California 92037.
Zhang
Wei
W
Scripps Research Institute, La Jolla, California 92037.
Chang
Yunchao
Y
Scripps Research Institute, La Jolla, California 92037.
Vega
Jose Antonio
JA
Universidad San Pablo-CEU, Madrid, Spain.
Deuel
Thomas F
TF
Scripps Research Institute, La Jolla, California 92037. Electronic address: tfdeuel@scripps.edu.
D000077548:Anaplastic Lymphoma Kinase; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D002352:Carrier Proteins; D016207:Cytokines; D008024:Ligands; C066845:pleiotrophin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C516895:PTPRZ1 protein, human; D017027:Protein Tyrosine Phosphatases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5