Human Cataract Mutations in EPHA2 SAM Domain Alter Receptor Stability and Function

The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity

Rayleigh Wave Attenuation Tomography in the Crust of the Chinese Mainland

Abstract In this study, we report a first major effort to measure surface wave amplitudes and to map attenuation structures of the Chinese mainland with dense modern broadband seismic networks in the country. We developed a method of phase‐matched filtering to automatically extract fundamental‐mode Rayleigh waves and to measure the spectral amplitudes. The results are compatible with those from the previous manual method with great improvement in efficiency. Using the automatic method, we extracted a large quantity of the amplitudes of Rayleigh waves at periods of 10 and 20 s recorded by 141 broadband stations from the China Digital Seismograph Network and 656 broadband stations from the China Regional Seismic Network. We performed tomographic inversions using the method of two‐station amplitude ratios and obtained images of the surface wave attenuation maps at periods of 10 and 20 s for the Chinese mainland. The tomographic model resolution reaches 1–2° in central and eastern China, 3–5° in western China, and 5° in the southeastern margin of the Tibetan Plateau and northeastern China. The tomographic results demonstrate good correspondence with geological structures. The distribution of strong historical earthquakes indicates that in the Chinese mainland, these earthquakes occurred mainly in high‐attenuation areas or the junctions between high‐ and low‐attenuation areas