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SHP1 is a non-receptor protein tyrosine phosphatase that is widely expressed in hematopoietic cells such as white blood cells, neutrophils, and immune cells. SHP1 can regulate the occurrence and differentiation of immune cells and plays an important role as a tumor suppressor. Previous studies have suggested that SHP2, the homologous protein of phosphatase SHP1, can undergo liquid-liquid phase separation (LLPS). Therefore, in this study, we investigated if SHP1 is also capable of LLPS. To the best of our knowledge, our study is the first to reveal that SHP1 has the ability to undergo LLPS. In addition, we identified an important residue, SHP1-R360E, that can completely inhibit the LLPS ability of SHP1, but this mutation has no remarkable effect on SHP1's enzymatic activity. This allows us to explore the phosphatase activity and phase separation ability of SHP1 separately, providing a basis for future exploration of the phase separation mechanism of phosphatases., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted., Competing Interests: Declaration of Interests J.Z. is a co-founder of Etern Biopharma Co. Ltd. and a member of its scientific advisory board. Q.Z. is a consultant to Etern Biopharma Co. Ltd. L.D. is an employee of Etern Biopharma Co. Ltd. H.C.S. is an employee of Roche. Etern Biopharma Co. Ltd. holds the patent WO-2020094018 that includes ET070 as one exemplified compound., (Copyright © 2020 Elsevier Inc. All rights reserved.)

SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric, and breast cancers. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells. In this study, we report the identification of an allosteric SHP2 inhibitor 1-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-4-methylpiperidin-4-amine (23) that locks SHP2 in a closed conformation by binding to the interface of the N-terminal SH2, C-terminal SH2, and phosphatase domains. Compound 23 suppresses MAPK signaling pathway and YAP transcriptional activity and shows antitumor activity in vivo. The results indicate that allosteric inhibition of SHP2 could be a feasible approach for cancer therapy.