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PreprintCC BYbioRxiv

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

  • Mukesh Kumar Venkat Ramani1,2
  • Philipp Ross1,2
  • Kailin Guo3
  • Yannik Leuz4
  • Jillian Bonilla2
  • Haley Hardtke1,2
  • Juan L Mendoza1,2,4
4 affiliations
  1. 1Howard Hughes Medical Institute at University of Chicago, Chicago, IL, USA
  2. 2Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
  3. 3Department of Biophysical Sciences, University of Chicago, Chicago, IL, USA
  4. 4Department of Biochemistry and Molecular Biology, University of Chicago, IL, USA
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Abstract

Cytokine receptors signal through a dedicated Janus kinase (JAK) that is thought to be constitutively bound to the receptor intracellular domain (ICD). We tested this one-receptor, one-JAK model biophysically. A bead-based screen of JAK1 and TYK2 against 32 receptor ICDs, confirmed by microscale thermophoresis to measure affinity, revealed dissociation constants spanning tens of nanomolar to tens of micromolar, indicating that many interactions are not high-affinity and may not be constitutive. Binding was also widely cross-reactive: GMCSFR bound both JAK1 and TYK2, and IL2R{beta} bound TYK2 far more tightly than JAK1. In cells, GM-CSF signaled through JAK1 when JAK2, JAK3, and TYK2 were inhibited. JAK-receptor pairing is therefore permissive and graded rather than exclusive and constitutive.

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Cite

BibTeXRIS
BibTeX
@misc{ramani2026graded,
  title = {{Graded and cross-reactive JAK-receptor interactions broaden the one-receptor, one-JAK rule}},
  author = {Mukesh Kumar Venkat Ramani and Philipp Ross and Kailin Guo and Yannik Leuz and Jillian Bonilla and Haley Hardtke and Juan L Mendoza},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.24.761551},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.24.761551v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Graded and cross-reactive JAK-receptor interactions broaden the one-receptor, one-JAK rule
AU  - Mukesh Kumar Venkat Ramani
AU  - Philipp Ross
AU  - Kailin Guo
AU  - Yannik Leuz
AU  - Jillian Bonilla
AU  - Haley Hardtke
AU  - Juan L Mendoza
PY  - 2026
DA  - 2026/10/24
PB  - bioRxiv
DO  - 10.64898/2026.10.24.761551
UR  - https://www.biorxiv.org/content/10.64898/2026.10.24.761551v1
AB  - Cytokine receptors signal through a dedicated Janus kinase (JAK) that is thought to be constitutively bound to the receptor intracellular domain (ICD). We tested this one-receptor, one-JAK model biophysically. A bead-based screen of JAK1 and TYK2 against 32 receptor ICDs, confirmed by microscale thermophoresis to measure affinity, revealed dissociation constants spanning tens of nanomolar to tens of micromolar, indicating that many interactions are not high-affinity and may not be constitutive. Binding was also widely cross-reactive: GMCSFR bound both JAK1 and TYK2, and IL2R{beta} bound TYK2 far more tightly than JAK1. In cells, GM-CSF signaled through JAK1 when JAK2, JAK3, and TYK2 were inhibited. JAK-receptor pairing is therefore permissive and graded rather than exclusive and constitutive.
SN  - 2692-8205
ER  -