Differential functional coupling in Gp130-JAK complexes expands the plasticity of the interleukin-6 signaling axis

Abstract

Cytokines dimerize/oligomerize surface receptors to activate signaling. While cytokine receptors preferentially bind only one member of the JAK family, ancestral cytokine receptors, such as Gp130, promiscuously recruit different JAKs to elicit their activities. Here, we have explored how the identity of JAKs in Gp130 signaling complexes can regulate functional outcomes. Using a synthetic biology approach, we show that Gp130 bound to different JAKs propagates distinct STAT activation profiles. While Gp130-JAK1 complexes activated both, STAT1 and STAT3 very potently, Gp130-JAK2 complexes exhibited a clear preference for STAT3 activation. Gp130-TYK2 complexes triggered overall weaker signaling but with diminished STAT specificity. The three JAKs competed for binding to Gp130 and led to differential activation of phospho-Tyr in the Gp130 intracellular domain. JAK1, JAK2 and to a lower extent TYK2 bound with comparable affinities to Gp130, and in response to IL-6 stimulation efficiently drove Gp130 dimerization. However, the three JAKs differentially affected Gp130 surface expression, identifying JAK-dependent receptor trafficking as a critical determinant of signaling plasticity. Our results provide new mechanistic insights into how differential functional coupling in Gp130-JAK complexes translates into unique signaling signatures that likely contribute to its large functional diversity.

Specificity and promiscuity of JAK recruitment regulates pleiotropy of cytokine-receptor signaling

“…Yet, the potency of downstream signaling by TPOR showed striking differences for different JAK homodimers, which has previously also been related to differential orientational constraints required for functional pairing ( 69 ). Similarly, differential functional coupling of GP130 via different JAK homodimers has recently been described ( 60 ). We therefore expect that modulation of cytokine receptor activity by promiscuous JAK binding may apply relatively broadly, which can explain the pronounced pleiotropy common in this family ( 5 , 16 , 48 , 60 , 66 , 67 , 70 ).…”

“…Similarly, differential functional coupling of GP130 via different JAK homodimers has recently been described ( 60 ). We therefore expect that modulation of cytokine receptor activity by promiscuous JAK binding may apply relatively broadly, which can explain the pronounced pleiotropy common in this family ( 5 , 16 , 48 , 60 , 66 , 67 , 70 ). modulation of IFNAR signaling by differential JAK recruitments as characterized in this study opens a new perspective into the tunable nature of IFN-I signaling.…”

“…Our data suggest that rather than receptor binding, receptor trafficking and/or efficiency in cross-talk between different JAKs in the signaling complex are responsible for such differential activity. Promiscuity of JAK binding has been reported for several cytokine receptors (56)(57)(58)(59), but its role in differentially regulating downstream signaling has hardly been appreciated (59)(60)(61). We propose that differential JAK recruitment may be a common principle, which may be overlooked due to a lack of suitable in situ receptor binding assays.…”