Graded and cross-reactive JAK-receptor interactions broaden the one-receptor, one-JAK rule

Bead-based screening of JAK1 and TYK2 against 32 cytokine receptor ICDs shows dissociation constants spanning tens of nanomolar to tens of micromolar, indicating many interactions are not high-affinity or constitutive.

• Why it matters: The work tests the “one-receptor, one-JAK” model that assumes dedicated, constitutively bound JAKs, addressing whether real receptor–JAK interactions are exclusive and uniformly strong.
• What they did: JAK1 and TYK2 were screened against 32 receptor ICDs on beads, with microscale thermophoresis used to measure affinities and assess cross-reactivity across receptor subunits.
• The result: Binding is widely cross-reactive (GMCSFR binds both JAK1 and TYK2; IL2R{beta} binds TYK2 far more tightly than JAK1), and in cells GM-CSF signals through JAK1 when JAK2, JAK3, and TYK2 are inhibited.