The activation mechanism of the phosphatase SHP-2 by PD-1: a molecular view on cancer immune-escape

• Applicant: Professorin Dr. Teresa Carlomagno
• Subject Area: Structural Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412348685

Protein tyrosine phosphatases (PTPs) play key roles in numerous cellular processes. The PTP cytoplasmic Src homology 2 domain-containing phosphatase 2 (SHP-2) is involved in various kinds of leukemias and solid tumors, and is emerging as an important target for anticancer therapy. SHP-2 is also a key mediator of inhibitory receptor signaling, through its interaction with immune checkpoint receptors like the programmed death-1 (PD-1). PD-1 functions to control excessive immune activation; in addition it provides a means by which tumors evade the immune system. Recent evidence supports the notion that inhibition of either SHP-2 or PD-1 activity is sufficient to restore T cell activation, thereby allowing for the immune system to attack the tumor. In this context, studying the interaction of SHP-2 with PD-1 becomes relevant as a possible pathway to inhibit cancer immune escape. SHP-2 consists of three domains and a disordered C-terminal tail. Two domains, the N-SH2 and C-SH2, are able to bind phosphopeptides; the PTP domain contains the catalytic cleft and is responsible for the enzymatic activity, while the C-terminal disordered tail has a regulatory role. In this project, we study the activation mechanism of SHP-2 by the phosphorylated cytoplasmatic tail of PD-1, which is mediated by the divalent interaction of the tail with the two SH2 domains. We use structure biology, biophysical, biochemical and cellular assays to answer structural and mechanistic questions concerning the role of either of the SH2 domains in the activation process, as well as the conformational changes accompanying stimulation and regulation of SHP-2 activity. Our aim is to provide an understanding of the mechanism of activation of SHP-2 by PD-1 at the atomic structural level.

• DFG Programme: Research Grants
• International Connection: United Kingdom