Functions of Shp2 in cancer

Abstract

Diagnostics and therapies have shown evident advances. Tumour surgery, chemotherapy and radiotherapy are the main techniques in treat cancers. Targeted therapy and drug resistance are the main focus in cancer research, but many molecular intracellular mechanisms remain unknown. Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) is associated with breast cancer, leukaemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, oral cancer and other cancer types. Signalling pathways involving Shp2 have also been discovered. Shp2 is related to many diseases. Mutations in the ptpn11 gene cause Noonan syndrome, LEOPARD syndrome and childhood leukaemia. Shp2 is also involved in several cancer-related processes, including cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance. Based on the structure and function of Shp2, scientists have investigated specific mechanisms involved in cancer. Shp2 may be a potential therapeutic target because this phosphatase is implicated in many aspects. Furthermore, Shp2 inhibitors have been used in experiments to develop treatment strategies. However, conflicting results related to Shp2 functions have been presented in the literature, and such results should be resolved in future studies.

Keywords: DNA damage; Shp2; apoptosis; cancer; cell proliferation; drug resistance; invasion and metastasis.

Figure 1

Schematic diagram of the signalling and functions of Shp2 (1). In the presence of extracellular stimulation, including some cytokines and growth factors [e.g. interleukin (IL)6, epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), IFN), they binds to relevant receptor to activate the down-stream, as a result, Shp2 can be phosphorylated by the receptor tyrosine kinase (RTK), p-Shp2 binds to the Grb2/SOS to activate the Ras/Erk signalling, so that to enhance tumour invasion and metastasis. PTP activation and pTyr of Shp2 are the focus of research work, with a lot of conflicted results, it is not sure how Shp2 functions in different microenvironments, although signalling molecular inhibitors can treat and work partly, but it is necessary to ensure the safety and control the compensatory. (2) Gab1 can bind to Shp2 and activate the PI3K/Akt signalling to regulate tumour cell proliferation, tumour apoptosis and drug resistance. And still, the phosphatase activity of Shp2 plays a critical role in controlling these processes. (3) Shp2 participates in p53 signalling to regulate DNA damage and replication in cancer. (4) Stat3 can be phosphorylated to form dimer, Shp2 can dephosphorylate Stat3, but p-Stat3 is important for tumour progress, so the relationship and mechanism between p-Stat3 and Shp2 should be further investigated, and gives a more reasonable explaining for future research.