TABLE 1.
Gain/loss-of-function mutations of SHP2.
| Mutants | Disease | Influences and mechanisms | Function | References |
| D61G | / | SHP2D61G promotes U251 proliferation and inhibits apoptosis | GOF | Zhao et al., 2017 |
| D61G | / | SHP2D61G enhances the production of ROS, leading to abnormal proliferation of bone marrow | GOF | Xu et al., 2013 |
| D61G | JMML | JMML is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. SHP2D61G promotes abnormal activation of hematopoietic stem cells and leads to JMML | GOF | Xu et al., 2010 |
| D61G | NS | NS is a multisystem developmental disease. Patients with NS tend to develop JMML. SHP2D61G promotes hyperactivation of Ras/Erk1/2 to inhibit GH-induced IGF-1 release, leading to growth retardation and NS | GOF | De Rocca Serra-Nédélec et al., 2012 |
| D61G | Breast cancer | SHP2D61G activates GAB1/Ras/Erk axis to promote breast cancer invasion and migration | GOF | Hu et al., 2016 |
| D61Y | JMML | SHP2D61Y promotes the cell cycle development and survival of hematopoietic progenitor cells and further leads to JMML | GOF | Yang et al., 2008 |
| E76K | JMML | SHP2E76K promotes the cell cycle development and survival of hematopoietic progenitor cells | GOF | Yang et al., 2008 |
| E76K | GBM | GBM is the most aggressive and common form of brain malignancy in adults. SHP2E76K activates the Erk/CREB pathway to promote GBM cell proliferation, metastasis, and tumor growth | GOF | Yang et al., 2019 |
| E76K | / | SHP2E76K leads to mitotic abnormalities | GOF | Liu et al., 2016 |
| E76K | / | SHP2E76K promotes lung tumor development in transgenic mice | GOF | Schneeberger et al., 2014 |
| E76K | / | SHP2E76K enhances the production of ROS, leading to abnormal proliferation of bone marrow | GOF | Xu et al., 2013 |
| E76K | / | SHP2E76K has a non-pedigree-specific effect on hematopoietic malignant transformation and leads to acute leukemia in every stage of hematopoiesis | GOF | Xu et al., 2011 |
| E76K | CRC | The mutation rate of SHP2 is the highest in CRC. SHP2E76K promotes tumorigenesis and induces EMT through the Wnt/β-catenin signaling pathway | GOF | Zhang et al., 2018 |
| E76K | Hydrocephalus | SHP2E76K promotes the pathogenesis of hydrocephalus in mice by inhibition of STAT3 and enhancement of Erk/Akt activity. SHP2C459S suppresses this pathogenic effect | GOF | Zheng et al., 2018 |
| E76Q | / | Phosphatase activity of SHP2E76Q was enhanced | GOF | Rehman et al., 2019 |
| T507K | / | SHP2T507K dephosphorylates Sprouty1 to hyperactive Ras signaling pathway | GOF | Zhang et al., 2020 |
| Q506P | / | Phosphatase activity of SHP2Q506P is reduced | LOF | Noda et al., 2016 |
| Q510E | HCM | Dysregulation of mTOR signal pathway mediated by SHP2Q510E causes HCM, which is a common inherited cardiovascular disease | LOF | Schramm et al., 2012 |
| Q510E | HCM | SHP2Q510E mutation reduces cardiac cell differentiation and promotes cardiac hypertrophy by disabling Akt/GSK-3/β-catenin signaling pathway | LOF | Ishida et al., 2011 |
| T468M | / | Phosphatase activity of SHP2T468M is reduced | LOF | Noda et al., 2016 |
| Y279C | / | Phosphatase activity of SHP2Y279C is reduced | LOF | Xu et al., 2010 |
NS, Noonan syndrome; JMML, juvenile myelomonocytic leukemia; CRC, colorectal cancer; GBM, glioblastoma multiforme; HCM, hypertrophic cardiomyopathy; LOF, loss of function; GOF, gain of function; EMT, epithelial-to-mesenchymal transition.