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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02468

SHP-2 in lymphocytes’ cytokine and inhibitory receptor signaling

 Greta Guarda1, 2*,  Charlène Niogret3 and Walter Birchmeier4
  • 1Biochemistry, Institute for Research in Biomedicine (IRB), Switzerland
  • 2Università della Svizzera italiana, Switzerland
  • 3Université de Lausanne, Switzerland
  • 4Max Delbrück Center for Molecular Medicine, Helmholtz Association of German Research Centers (HZ), Germany

Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby exerting essential developmental functions. This phosphatase also deploys proto-oncogenic functions and specific inhibitors have recently been developed. With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied. The function of this phosphatase downstream of cytokines important for lymphocytes is less understood, though multiple lines of evidence suggest its importance. In addition, SHP-2 has been proposed to mediate the suppressive effects of inhibitory receptors (IRs) that sustain a dysfunctional state in anticancer T cells. Molecules involved in IR signaling are of potential pharmaceutical interest as blockade of these inhibitory circuits leads to remarkable clinical benefit. Here, we discuss the dichotomy in the functions ascribed to SHP-2 downstream of cytokine receptors and IRs, with a focus on T and NK lymphocytes. Further, we highlight the importance of broadening our understanding of SHP-2’s relevance in lymphocytes, an essential step to inform on side effects and unanticipated benefits of its therapeutic blockade.

Keywords: SHP-2 phosphatase, SHP-2 inhibitors, PTPN11 gene, T cell, NK cell, cytokine, Inhibitory receptors of lymphocytes, PD-1, signaling, Cancer

Received: 03 Jul 2019; Accepted: 03 Oct 2019.

Copyright: © 2019 Guarda, Niogret and Birchmeier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Greta Guarda, Institute for Research in Biomedicine (IRB), Biochemistry, Bellinzona, 1066, Switzerland, greta.guarda@irb.usi.ch