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A ligand-inducible anaplastic lymphoma kinase chimera is endocytosis impaired

Oncogene volume 23, pages 1098–1108 (2004)Cite this article

Abstract

Ligand-induced membrane trafficking of the anaplastic lymphoma kinase (ALK) was studied using a chimeric receptor in which the extracellular and transmembrane domain of ALK was substituted for the corresponding regions of epidermal growth factor receptor (EGFR). Wild-type EGFR, EGFR/ALK and an EGFR/ALK kinase negative mutant were independently expressed in mouse NR6 fibroblasts. The capacity of EGFR/ALK to mediate [125I]-EGF internalization, receptor degradation and downregulation, which has never been previously described, was assayed. The rate of [125I]-EGF-induced internalization mediated by the cytoplasmic domain of ALK was reduced several fold compared with the wild-type EGFR. The low rate of EGF internalization promoted by EGFR/ALK correlated with an impaired degradation and downregulation of the receptor and indicate that ALK is not subject to traditional mechanisms used to regulate receptor tyrosine kinase function. Accordingly, ALK-activated intracellular domain does not associate in vivo with c-cbl and does not undergo ligand-mediated ubiquitination. The current study provides new insight into the function and regulation of ALK suggesting that the relative long membrane residence of activated ALK might confers a more potent and prolonged signaling activity. Indeed NR6-EGFR/ALK cells exhibited a ∼3-fold increase in a maximal mitogenic response than NR6-EGFR.

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Abbreviations

ALCL:

anaplastic large cell lymphoma

ALK:

anaplastic lymphoma kinase

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

PTyr:

phosphotyrosine

RTK:

receptor tyrosine kinase

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Acknowledgements

We are grateful to Professor A Rappelli for his continues support and encouragement during the course of this work. We also thank Professor PP Pelicci and Professor B Falini for providing us with the anti-alk monoclonal antibody. The authors appreciate the excellent assistance of Dr R Bacchiocchi, D Carbonari and M Cesaroni. This research was fully supported by grant from the Associazione Italiana Ricerca sul Cancro. MS is supported by a Fellowship from Fondazione Italiana Ricerca Cancro.

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  1. Laboratory of Cellular and Molecular Biology, Institute of Clinical Medicine, University of Ancona, Via Tronto 10/A, Ancona, 60020, Italy

    Michela Serresi, Gina Piccinini, Elisa Pierpaoli & Francesca Fazioli

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  1. Michela Serresi
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  2. Gina Piccinini
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Correspondence to Francesca Fazioli.

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Serresi, M., Piccinini, G., Pierpaoli, E. et al. A ligand-inducible anaplastic lymphoma kinase chimera is endocytosis impaired. Oncogene 23, 1098–1108 (2004). https://doi.org/10.1038/sj.onc.1207227

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