Abstract
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.
Highlights
Protein phosphorylation is a post-translational modification fundamental for intracellular signaling cascades and is tightly regulated by kinases and phosphatases
We focus on the role of SHP-2 in T and natural killer (NK) lymphocytes, which are crucial players in immunity and in anticancer immunotherapy
Later studies showed that the same gp130 binding site recruited the Janus kinases (JAKs) inhibitor Suppressor of cytokine signaling 3 (SOCS3), attributing to the latter the antagonism with STAT3, and confounding the role of SHP-2 [113, 114]
Summary
Protein phosphorylation is a post-translational modification fundamental for intracellular signaling cascades and is tightly regulated by kinases and phosphatases. RAS tyrosine phosphorylation at position 32 negatively impacts on downstream signaling, possibly by favoring the interaction with RAS-GAP; by removing this modification, SHP-2 promotes ERK activation (Figure 2B) [52]. SHP-2 has been reported to modulate the phosphorylation of signal transducers and activators of transcription (STAT) transcription factors downstream of various cytokines (Figure 3) [73].
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