Search

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.

In this paper, the linear free flexural vibrations of functionally graded material plates with a through center crack is studied using an 8-noded shear flexible element. The material properties are assumed to be temperature dependent and graded in the thickness direction. The effective material properties are estimated using the Mori-Tanaka homogenization scheme. The formulation is developed based on first-order shear deformation theory. The shear correction factors are evaluated employing the energy equivalence principle. The variation of the plates natural frequency is studied considering various parameters such as the crack length, plate aspect ratio, skew angle, temperature, thickness and boundary conditions. The results obtained here reveal that the natural frequency of the plate decreases with increase in temperature gradient, crack length and gradient index. © 2011 Elsevier Ltd. All rights reserved.

In this paper, the linear free flexural vibrations of functionally graded material plates with a through center crack is studied using an 8-noded shear flexible element. The material properties are assumed to be temperature dependent and graded in the thickness direction. The effective material properties are estimated using the Mori-Tanaka homogenization scheme. The formulation is developed based on first-order shear deformation theory. The shear correction factors are evaluated employing the energy equivalence principle. The variation of the plates natural frequency is studied considering various parameters such as the crack length, plate aspect ratio, skew angle, temperature, thickness and boundary conditions. The results obtained here reveal that the natural frequency of the plate decreases with increase in temperature gradient, crack length and gradient index. © 2011 Elsevier Ltd. All rights reserved.