Regulation and activity of the phosphatase SHP2: SH2 domains, dephosphorylation activity, and beyond

Src homology 2 (SH2) domain-containing phosphatase-2 (SHP2, PTPN11) is implicated in diseases such as cancer and RASopathies, where it is often mutated. It has gained strong attention due to promising new drug development strategies, with drug candidates currently in clinical trials. SHP2 is activated downstream of cell surface receptors to promote signaling pathways involved in cell growth and to inhibit immune cell activation. The phosphatase has two SH2 domains and a protein tyrosine phosphatase (PTP) domain, is post-translationally modified, and can function as an active phosphatase or as an adaptor/scaffold protein. It is subject to tight regulation in its cellular environment, for which novel insights have recently emerged. In this focused review, we first summarize the roles of the two SH2 domains and phosphorylation on the regulation of wildtype SHP2. We then describe new developments concerning catalytic and non-catalytic functions of SHP2, as well as recent progress in the understanding of SHP2 regulation, including it being subjected to SUMOylation, activated independently of cell surface receptors, and regulated by substrate phosphorylation. These new insights not only demonstrate the complexity of SHP2 regulation but also guide future studies, contributing important insights that could aid in targeting SHP2 in different disease contexts in the future.