PTPN11

PTPN11 encodes the protein tyrosine phosphatase SHP2, which has a modular structure essential for its regulatory function in cell signaling. SHP2 consists of two tandem Src homology 2 (SH2) domains at the N-terminus (N-SH2 and C-SH2), followed by a catalytic protein tyrosine phosphatase (PTP) domain and a C-terminal tail containing tyrosyl phosphorylation sites. In its inactive, auto-inhibited conformation, the N-SH2 domain binds intramolecularly to the PTP catalytic domain, blocking substrate access to the active site. The overall structure has been elucidated by multiple crystallographic studies, revealing both the auto-inhibited and active states, which provide insight into its mechanism of regulation and function in diverse cellular contexts. == Function ==

PTPN11 encodes SHP2, a ubiquitously expressed protein tyrosine phosphatase that plays an important role in regulating cell signaling pathways, most notably the RAS/MAPK cascade, which controls cell proliferation, differentiation, migration, and survival. SHP2 acts as a positive regulator of signal transduction by dephosphorylating specific phosphotyrosine residues on target proteins, thereby facilitating the propagation of growth factor and cytokine signals. In cancer, SHP2 can function as an oncogenic driver by sustaining RAS/RAF/MAPK signaling and supporting tumor cell growth and survival. Thus, PTPN11/SHP2 is a critical regulator of both normal cellular processes and disease states, with its dysregulation contributing to developmental syndromes and oncogenesis. == Clinical significance ==

Missense mutations in the PTPN11 locus are associated with both Noonan syndrome and Leopard syndrome. At least 79 disease-causing mutations in this gene have been discovered. Noonan syndrome In the case of Noonan syndrome, mutations are broadly distributed throughout the coding region of the gene but all appear to result in hyper-activated, or unregulated mutant forms of the protein. Most of these mutations disrupt the binding interface between the N-SH2 domain and catalytic core necessary for the enzyme to maintain its auto-inhibited conformation. ===Noonan syndrome with multiple lentigines=== The mutations that cause Noonan syndrome with multiple lentigines (formerly known as leopard syndrome) are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants. It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes. Metachondromatosis It has also been associated with metachondromatosis. Cancer Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemias (JMML). Activating Shp2 mutations have also been detected in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colorectal cancer. Recently, a relatively high prevalence of PTPN11 mutations (24%) were detected by next-generation sequencing in a cohort of NPM1-mutated acute myeloid leukemia patients, although the prognostic significance of such associations has not been clarified. These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor. The bacterium Helicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factor CagA with SHP2. H Pylori CagA virulence factor CagA is a protein and virulence factor inserted by Helicobacter pylori into gastric epithelia. Once activated by SRC phosphorylation, CagA binds to SHP2, allosterically activating it. This leads to morphological changes, abnormal mitogenic signals and sustained activity can result in apoptosis of the host cell. Epidemiological studies have shown roles of cagA- positive H. pylori in the development of atrophic gastritis, peptic ulcer disease and gastric carcinoma. == Interactions ==

PTPN11 has been shown to interact with • CagA, • CD117, • CD31, • CEACAM1, • Epidermal growth factor receptor, • Erk • FRS2, • GAB1, • GAB2, • GAB3, • Glycoprotein 130, • Grb2, • Growth hormone receptor, • HoxA10, • Insulin receptor, • Insulin-like growth factor 1 receptor, • IRS1, • Janus kinase 1, • LAIR1, • LRP1, • PDGFRB, • PI3K → Akt • PTK2B, • Ras • SOCS3, • STAT3, and • STAT5B. ==Ligands==

;Inhibitors • Batoprotafib • SHP099 • Sitneprotafib • Vociprotafib (RMC-4630) ;AUTACs • SA-8 == References ==