Differential requirement for type I and type II transforming growth factor β receptor kinase activity in ligand-mediated receptor endocytosis

Robert A. Anders, Jules J.E. Doré, Sandra L. Arline, Nandor Garamszegi, Edward B. Leof

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Transforming growth factor β (TGFβ) superfamily polypeptides regulate cell growth and differentiation by binding to single pass serine/threonine kinases referred to as TGFβ type I and type II receptors. Signal propagation is dependent upon heteromeric (type I-type II) complex formation and transphosphorylation of the type I receptor by the type II receptor. While many of the phosphorylation events necessary for receptor signaling have recently been characterized, the role of TGFβ receptor kinase activity in modulating receptor endocytosis has not been addressed. To that end, we have used chimeric receptors consisting of the extracellular domain of the granulocyte/macrophage colony-stimulating factor α and β receptors spliced to the TGFβ type I and type II transmembrane and cytoplasmic domains to address the specific role of type I and/or type II receptor kinase activity in TGFβ receptor internalization, downregulation, and signaling. To inactivate chimeric receptor kinase activity, point mutations in the ATP binding site were made at amino acids 232 and 277 in the type I and type II receptor, respectively. Either of these mutations abolished plasminogen activator inhibitor 1 protein expression stimulated by granulocyte/macrophage colony-stimulating factor activation of chimeric heteromeric type I-type II TGFβ receptors. They did not, however, modulate TGFβ signaling stimulated through the endogenous TGFβ receptor. Although TGFβ receptor signaling was dependent upon the kinase activity of both chimeric receptors, the initial endocytic response was distinctly regulated by type I and/or type II receptor kinase activity. For instance, while heteromeric receptor complexes containing a kinase-inactive type I receptor were endocytosed similarly to wild type complexes, the kinase activity of the type II TGFβ receptor was necessary for optimal internalization and receptor down-regulation. Furthermore, these responses were shown to occur independently of type II receptor autophosphorylation but require a type II receptor capable of transphosphorylation.

Original languageEnglish (US)
Pages (from-to)23118-23125
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number36
DOIs
StatePublished - Sep 4 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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