Forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth.
Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based on IL-15/IL-15R alpha-sushi fusion proteins. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR, and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 and factor-independent growth of stably transduced Ba/F3-gp130 cells. Here, we establish the IL-15/IL-15R alpha-sushi system as a new system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which might be applicable to other heterodimeric receptor families. A mutated IL-15 protein, which was still able to bind the IL-15R alpha-sushi domain, but not to beta- and gamma-receptor chains, in combination with the 2A peptide technology may be used to translate our in vitro data into the in vivo situation to assess the tumorigenic potential of gp130-heterodimeric receptor complexes.
Suthaus
Jan
J
*Department of Biochemistry, Christian-Albrechts-Universität, D-24098 Kiel, Germany.
Tillmann
Anna
A
Lorenzen
Inken
I
Bulanova
Elena
E
Rose-John
Stefan
S
Scheller
Jürgen
J
D000818:Animals; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism; D008024:Ligands; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D055503:Protein Multimerization; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D016207:Cytokines; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D008024:Ligands; D046912:Multiprotein Complexes; D050791:STAT Transcription Factors; D050822:Cytokine Receptor gp130; D048049:Extracellular Signal-Regulated MAP Kinases