biostudies-literatureBarton MIWellcome Trust1138https://www.ebi.ac.uk/biostudies/studies/S-EPMC11399299biostudies-literatureUnknown7(1)Leukocytes interact with other cells using cell surface receptors. The largest group of such receptors are non-catalytic tyrosine phosphorylated receptors (NTRs), also called immunoreceptors. NTR signalling requires phosphorylation of cytoplasmic tyrosine residues by SRC-family tyrosine kinases. How ligand binding to NTRs induces this phosphorylation, also called NTR triggering, remains controversial, with roles suggested for size-based segregation, clustering, and mechanical force. Here we exploit a recently developed cell-surface generic ligand system to explore the ligand requirements for NTR triggering. We examine the effect of varying the ligand's length, mobility and valency on the activation of representative members of four NTR families: SIRPβ1, Siglec 14, NKp44 and TREM-1. IncreasCommunications biologyLigand requirements for immunoreceptor triggering.PMC11399299101799/Z/13/ZBarton MIDenham EMvan der Merwe PAGoyette JPaterson RLfalseLigand requirements for immunoreceptor triggering.Leukocytes interact with other cells using cell surface receptors. The largest group of such receptors are non-catalytic tyrosine phosphorylated receptors (NTRs), also called immunoreceptors. NTR signalling requires phosphorylation of cytoplasmic tyrosine residues by SRC-family tyrosine kinases. How ligand binding to NTRs induces this phosphorylation, also called NTR triggering, remains controversial, with roles suggested for size-based segregation, clustering, and mechanical force. Here we exploit a recently developed cell-surface generic ligand system to explore the ligand requirements for NTR triggering. We examine the effect of varying the ligand's length, mobility and valency on the activation of representative members of four NTR families: SIRPβ1, Siglec 14, NKp44 and TREM-1. Increas2024-01-01T00:00:00Z2024 Sep2025-04-04T09:49:31.296Z2025-04-04T09:49:31.296ZS-EPMC113992993927174410.1038/s42003-024-06817-y