2. Academic Validation
  3. Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation

Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation

  • Commun Biol. 2020 Mar 17;3(1):128. doi: 10.1038/s42003-020-0845-0.
Nikolaos Patsoukis 1 2,  Jonathan S Duke-Cohan 3,  Apoorvi Chaudhri 3 4,  Halil-Ibrahim Aksoylar 1 2,  Qi Wang 1 2,  Asia Council 1 2,  Anders Berg 5 6,  Gordon J Freeman 3,  Vassiliki A Boussiotis 7 8
Affiliations

Affiliations

  • 1 Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
  • 2 Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 4 MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
  • 5 Department of Pathology Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA, 02215, USA.
  • 6 Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • 7 Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. vboussio@bidmc.harvard.edu.
  • 8 Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. vboussio@bidmc.harvard.edu.
PMID: 32184441 DOI: 10.1038/s42003-020-0845-0
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.

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