Determinants governing the potency of STAT3 activation via the individual STAT3-recruiting motifs of gp130.
In recent years, the elucidation of the structures of many signalling molecules has allowed new insights into the molecular mechanisms that govern signal transduction events. In the field of cytokine signalling, the solved structures of cytokine/receptor complexes and of key components involved in signal transduction such as STAT factors or the tyrosine phosphatase SHP2 have broadened our understanding of the molecular basis of the signalling events and provided key information for the rational design of therapeutic approaches to modulate or block cytokine signal transduction. Unfortunately, no structural data on the intracellular parts of cytokine receptors are available. The exact molecular mechanism underlying one of the first steps in signal transduction, namely the recruitment of signalling components to the cytoplasmic parts of cytokine receptors, remains elusive. Here we investigated possible mechanisms underlying the different potency of the STAT3-activating motifs of gp130 after IL-6 stimulation. Our data indicate that the extent of STAT3 activation by the different receptor motifs is not influenced by structural features such as contacts between the two gp130 chains. In addition, the proximity of the negatively regulating motif around tyrosine Y759 to the different STAT3-recruiting motifs does not seem to be responsible for their differential capacity to activate STAT3. However, the potency of a specific motif to activate STAT3 directly reflects the affinity for the binding of STAT3 to this motif.
Lehmann
Ute
U
Institut für Biochemie, Universitätsklinikum der RWTH-Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Sommer
Ulrike
U
Smyczek
Tanya
T
Hörtner
Michael
M
Frisch
Wiltrud
W
Volkmer-Engert
Rudolf
R
Heinrich
Peter C
PC
Schaper
Fred
F
Haan
Serge
S
D020816:Amino Acid Motifs / Q000187:drug effects / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D014443:Tyrosine