Formation and activation by phosphorylation of activin receptor complexes.
Activin is a protein growth and differentiation factor that initiates intracellular events through the activation of a complex of transmembrane protein serine kinases. Two subfamilies of receptor serine kinases, type I and type II, have been identified, and both receptor types may be required to generate a transmembrane signal. Investigation of the interaction between various activin receptors (ActRs) revealed that ActRs I and II could exist in a stable complex and that formation of that complex between transiently overexpressed molecules was not regulated by ligand. Analysis of phosphorylation suggested that activin induced phosphorylation of receptor I, probably at residues within a conserved glycine and serine-rich sequence in the juxtamembrane region referred to as the GS domain. Phosphorylation of the GS domain was dependent upon a functional ActRII. Introduction of an activin type I receptor, ALK4, into the mink lung epithelial cell line, L17, conferred activin responsiveness on those cells. Mutation of specific combinations of serines and threonines in the core sequence of the ALK4 GS domain to alanine rendered that receptor incompetent for signaling. Mutation of the same sets of residues to glutamic acid produced molecules that supported activin signaling but that did not display elevated basal signaling anticipated for a constitutively active receptor. However, mutation of a threonine residue in the carboxy-terminal half of the GS domain, T206, to glutamic acid yielded receptors with constitutive activity. Taken together, these results support a role for phosphorylation of type I ActRs in the generation of a biological signal.
Willis
S A
SA
Department of Biological Chemistry, University of Michigan, Ann Arbor 48109-0606, USA.
Zimmerman
C M
CM
Li
L I
LI
Mathews
L S
LS
D029404:Activin Receptors; D030201:Activin Receptors, Type I; D028341:Activins; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D007265:Inhibins / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008907:Mink; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D016324:Sequence Tagged Sites; D012694:Serine; D015398:Signal Transduction; D013912:Threonine
D017931:DNA Primers; D006133:Growth Substances; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D028341:Activins; D013912:Threonine; D012694:Serine; D007265:Inhibins; D008715:Methionine; D008156:Luciferases; D029404:Activin Receptors; D030201:Activin Receptors, Type I