@article {1501372,
	title = {Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation},
	journal = {Commun Biol},
	volume = {3},
	number = {1},
	year = {2020},
	month = {2020 Mar 17},
	pages = {128},
	abstract = {Programmed cell death-1 (PD-1) inhibits T cell responses. This function relies on interaction with SHP-2. PD-1 has one immunoreceptor tyrosine-based inhibitory motif (ITIM) at Y223 and one immunoreceptor tyrosine-based switch motif (ITSM) at Y248. Only ITSM-Y248 is indispensable for PD-1-mediated inhibitory function but how SHP-2 enzymatic activation is mechanistically regulated by one PD-1 phosphotyrosine remains a puzzle. We found that after PD-1 phosphorylation, SHP-2 can bridge phosphorylated ITSM-Y248 residues on two PD-1 molecules via its amino terminal (N)-SH2 and carboxyterminal (C)-SH2 domains forming a PD-1: PD-1 dimer in live cells. The biophysical ability of SHP-2 to interact with two ITSM-pY248 residues was documented by isothermal titration calorimetry. SHP-2 interaction with two ITSM-pY248 phosphopeptides induced robust enzymatic activation. Our results unravel a mechanism of PD-1: SHP-2 interaction that depends only on ITSM-Y248 and explain how a single docking site within the PD-1 cytoplasmic tail can activate SHP-2 and PD-1-mediated inhibitory function.},
	issn = {2399-3642},
	doi = {10.1038/s42003-020-0845-0},
	author = {Patsoukis, Nikolaos and Duke-Cohan, Jonathan S and Chaudhri, Apoorvi and Aksoylar, Halil-Ibrahim and Wang, Qi and Council, Asia and Berg, Anders and Freeman, Gordon J and Boussiotis, Vassiliki A}
}
