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Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

Cross-talk between G protein-coupled receptors and receptor tyrosine kinase signaling pathways is crucial to the efficient relay and integration of cellular information. Here we identify and define the novel binding interaction of the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) with the GTP exchange factor ␤-p21-activated kinase-interactive exchange factor (␤PIX). We demonstrate that this interaction is mediated in part by the ␤PIX-SH3 domain binding to a proline-rich stretch of AIP4. Analysis of the interaction by isothermal calorimetry is consistent with a heterotrimeric complex with one AIP4-derived peptide binding to two ␤PIX-SH3 domains. We determined the crystal structure of the ␤PIX-SH3⅐AIP4 complex to 2.0-Å resolution. In contrast to the calorimetry results, the crystal structure shows a monomeric complex in which AIP4 peptide binds the ␤PIX-SH3 domain as a canonical Class I ligand with an additional type II polyproline helix that makes extensive contacts with another face of ␤PIX. Taken together, the novel interaction between AIP4 and ␤PIX represents a new regulatory node for G protein-coupled receptor and receptor tyrosine kinase signal integration. Our structure of the ␤PIX-SH3⅐AIP4 complex provides important insight into the mechanistic basis for ␤PIX scaffolding of signaling components, especially those involved in cross-talk.Two prominent transmembrane receptor families facilitate cellular communication with the extracellular environment: G protein-coupled receptors (GPCRs) 4 and receptor tyrosine kinases (RTKs). A wide array of ligands bind to these receptors to orchestrate signaling networks integral to many cellular functions. Internalization and degradation of receptor molecules from both families regulate signal duration and termination (1, 2). E3 ubiquitin ligases, which catalyze the ubiquitination of receptors, control intracellular sorting, recycling, and degradation (3-5). Representative E3 ligases include atrophininteracting protein 4 (AIP4), which ubiquitinates the GPCR chemokine receptor CXCR4 (6) and Cbl (Casitas B-lymphoma protein), which ubiquitinates the RTK epidermal growth factor (EGF) receptor (7-9). The importance of signal termination control is exemplified by recent work implicating prolonged signaling as a cause of cellular transformation (10, 11). In addition to mediating the ubiquitination and sorting of CXCR4, a number of recent studies detail the regulatory role AIP4 plays in developmental, immunological, and oncogenic signaling pathways (12-18). The AIP4/Itch protein is composed of an N-terminal C2 domain, followed by a proline-rich region, four WW domains, and a C-terminal catalytic HECT domain (3,4,12,13). AIP4 is abundantly expressed in most human tissues and displays tissue specificity similar to that of Cbl (19).␤-PAK-interactive exchange factor (␤PIX also referred to as Cool-1) is composed of modular domains, including an N-terminal SH3 domain followed by DH (Dbl, diffuse B-cell lymphoma homology) domain, PH (pleckstrin homology) domain, and a leucine...

Because of global warming and abnormal climate change, record-breaking heat wave events have been increasing. Therefore, it is necessary to analyze and predict the mechanisms for generating and developing heat waves. In this study, the impacts of synoptic and local factors on heat waves over the southeastern region of South Korea in 2015 are investigated. First, Heat wave events for 1980-2016 defined by spatiotemporal criteria are classified into three clusters using the K-means clustering analysis. Heat wave events in 2015 are compared to clusters of different synoptic conditions, which are strongly related to the western North Pacific subtropical high around South Korea. Second, numerical experiments using Weather Research and Forecasting model are performed to examine the effect of local conditions on 2015 heat waves. Four types of sensitivity experiments were conducted: a CTL experiment with no change in topography and soil moisture, TOPO experiment with lowered terrain, and WET and DRY experiments with wet and dry anomalies in initial soil moisture. The CTL experiment simulates higher temperature on the lee side compared to the TOPO experiment because of the Foehn effect. In particular, the effect is prominent when dry westerlies passing through mountains and the lower level atmosphere over the windward region are in a statically stable condition (i.e., nighttime). Due to the less (more) evaporation, the DRY (WET) experiment with less (more) soil moisture simulates higher (lower) maximum temperature than the CTL experiment during the daytime when solar radiation is relatively intense.Various studies have considered the impacts of large-scale factors on heat waves to identify mechanisms generating and developing heat waves. One major factor that causes heat wave events is the presence of large-scale anticyclone circulation over a specific area, producing low cloudiness, clear skies, and warm advection (Black et al., 2004;García-Herrera et al., 2010;Meehl & Tebaldi, 2004). The expansion of the western North Pacific subtropical high (WNPSH) has an important role in influencing summer extreme high temperatures over the East Asia summer monsoon region, including East China, South Korea, and Japan. Xue-zhao and Dao-yi (2002) determined