Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease

Abstract

Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.

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).…”

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

“…55,56 Somatic mutations in PTPN11 represent the most frequent molecular lesion identified to date in JMML, with up to 35% of JMML cases demonstrating PTPN11 mutations, often mutually exclusive with RAS or NF1 mutations. [57][58][59][60][61] Mouse models of these genetic lesions have proven their causal role in myeloproliferative disease development as well as hyperactivation of the Ras pathway and GM-CSF hypersensitivity. [62][63][64][65][66][67] The interested reader can see one of several recent reviews for a more in-depth review of these biochemical and genetic aberrations.…”

Reduced phosphatase activity of SHP‐2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1

“…In NS, most of SHP-2 mutations described so far affect residues located in or close to the interaction surface between the N-SH2 and the PTP domains [7]. This is thought to disrupt the autoinhibited closed conformation of SHP-2, resulting in an increased basal PTP activity of most NS-associated SHP-2 mutants observed in vitro [8,9].…”