The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

“…In this phosphatase assay, the E76K mutant of SHP-2, the most common leukemia-specific mutant that causes complete relief of autoinhibition and full activation (Neel et al, 2003;Keilhack et al, 2005;Tartaglia et al, 2006), exhibited more than 100-fold activity of wild-type SHP-2. In contrast, the T507K mutant showed only twofold increase in phosphatase activity compared with that of wild-type SHP-2 ( Figure 2b).…”

“…SHP-2 is a cytoplasmic protein tyrosine phosphatase (PTP) that plays a crucial role in signal transduction downstream of growth factor/cytokine receptors to regulate cellular responses, including proliferation, morphogenesis and cell motility (Neel et al, 2003). Biochemical and genetic evidence places SHP-2 upstream of RAS, and SHP-2 is required for full activation of RAS-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase signaling pathway.…”

“…In the basal state, SHP-2 is maintained in an inactive conformation by hydrophobic interaction between the N-SH2 domain and the PTP domain. Binding of a phosphotyrosinecontaining peptide to the N-SH2 domain alleviates the autoinhibition to form an open conformation with active phosphatase activity (Hof et al, 1998;Neel et al, 2003). Most if not all mutations found in Noonan syndrome or leukemia affect residues in the N-SH2 domain or PTP domain that abolish the autoinhibitory interaction and thereby exhibit increased basal phosphatase activity (Tartaglia et al, 2003).…”

MAP3Ks as central regulators of cell fate during development

“…Approximately 50% of all Noonan syndrome cases have mutations in the PTPN11 gene, which encodes the nonreceptor tyrosine phosphatase Shp2 (Tartaglia et al, 2004). This enzyme is a key component in several signaling pathways that control developmental processes such as cardiac valvulogenesis and hematopoietic cell differentiation (Neel et al, 2003). In individuals with Noonan syndrome that do not have mutations in the PTPN11 gene, the development of hypertrophic cardiomyopathy (CMH; OMIM#611553) has been linked to mutations in the C-Raf gene (Pandit et al, 2007).…”

Oxidative stress induces lipid-raft-mediated activation of Src homology 2 domain-containing protein-tyrosine phosphatase 2 in astrocytes

“…SHP-2 contains two Nterminal SH2 domains, a tyrosine phosphatase domain, and a Cterminal tail that contains two tyrosyl phosphorylation sites and a proline-rich region [10]. Phosphorylation of the C-terminal tyrosine residues by receptor and nonreceptor protein-tyrosine kinases is required for the adaptor function of SHP-2 and contributes to the regulation of its phosphatase activity in several signaling pathways [11].…”