TRK-T3 condensate organization drives growth signaling.

Oncogenic fusion proteins involving receptor tyrosine kinases can hijack cell signaling cascades to promote oncogenesis. Here, we show that the TRK-T3 fusion protein, generated by joining the N-terminal region of the condensate-forming protein TFG with the C-terminal region of TrkA, assembles into sheet-like biomolecular condensates after putative prewetting of the ER. These structures are distinct from those formed by either parent protein. We find that ER wetting and the condensate morphology of TRK-T3 are controlled by a hydrophobic transmembrane segment encoded in the TrkA moiety. Removing this segment abolishes the sheet-like morphology of TRK-T3 condensates in cells and in vitro. This loss of morphology diminishes the recruitment of the first-layer signal-transduction protein GRB2 and suppresses activation of the MAPK pathway. A minimal segment that mimics the transmembrane domain efficiently disrupts TRK-T3 condensation. Together, our findings highlight condensate morphology as an encoded property of this oncogenic fusion protein, controlling the alignment and signaling competence of TRK-T3 assemblies. They further suggest that hydrophobic interactions within TRK-T3 condensates represent a potential vulnerability in this oncogenic signaling mechanism.