A ligand-inducible anaplastic lymphoma kinase chimera is endocytosis impaired

Michela Serresi, Gina Piccinini, Elisa Pierpaoli, Francesca Fazioli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1098-1108
Number of pages11
JournalOncogene
Volume23
Issue number5
DOIs
Publication statusPublished - Feb 5 2004

Keywords

  • Downregulation
  • EGFR-ALK chimera
  • Internalization
  • Receptor degradation

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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