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J Biol Chem, Vol. 273, Issue 36, 23118-23125, September 4, 1998
Receptor Kinase Activity in Ligand-mediated Receptor
Endocytosis
From the Thoracic Research Unit and Department of Biochemistry and
Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905
Transforming growth factor 
(TGF)
superfamily polypeptides regulate cell growth and differentiation by
binding to single pass serine/threonine kinases referred to as TGF
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 TGF 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 
and receptors spliced to the TGF 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 TGF receptor internalization, down-regulation, 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 TGF receptors. They did not, however, modulate TGF signaling stimulated through the endogenous TGF receptor. Although TGF 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 TGF 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.
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