Glypican-3 (GPC3) is a heparan sulfate proteoglycan that is bound to the cell membrane by a glycosyl-phosphatidylinositol anchor. GPC3 is expressed by most hepatocellular carcinomas but not by normal hepatocytes and benign liver lesions. We report here that GPC3 stimulates the in vitro and in vivo growth of hepatocellular carcinoma cells by increasing autocrine/paracrine canonical Wnt signaling. Coimmunoprecipitation experiments showed that GPC3 is able to form complexes with Wnts, and cell-binding assays indicated that GPC3-expressing cells have an increased capacity to bind Wnt. Collectively, these results suggest that GPC3 stimulates Wnt activity by facilitating the interaction of this polypeptide with its signaling receptors. Surprisingly, in contrast to the current model that proposes that Wnt-glypican binding is mediated by the heparan sulfate chains, we found that the nonglycanated GPC3 core protein can form complexes with Wnts. Furthermore, we showed that the glycosaminoglycan chains are not required for the stimulatory effect on Wnt signaling and hepatocellular carcinoma growth. (Cancer Res 2005; 65(14): 6245-54)

The use of advanced analytical and numerical modelling in structural engineering has increased rapidly in recent years. A key feature of these models is an accurate description of the material stress-strain behaviour. Development of standardised constitutive equations for the full engineering stress-strain response of hot-rolled carbon steels is the subject of the present paper.The proposed models, which offer different options for the representation of the strain hardening region, feature an elastic response up to the yield point, followed by a yield plateau and strain hardening up to the ultimate tensile stress. The Young's modulus E, the yield stress fy and the ultimate stress fu are generally readily available to the engineer, but other key parameters, including the strains at the onset of strain hardening and at the ultimate stress, are not, and hence require predictive expressions. These expressions have been developed herein and calibrated against material stress-strain data collected from the literature. Unlike the widely used ECCS model, which has a constant length of yield plateau and constant strain hardening slope, the proposed models, reflecting the collected test data, have a yield plateau length and strain hardening characteristics which vary with the ratio of yield to ultimate stress (i.e. with material grade). The proposed models require three basic input parameters (E, fy and fu), are simple to implement in analytical or numerical models, and are shown herein to be more accurate than the widely employed ECCS model. The proposed models are based on and hence representative of modern hot-rolled steels from around the world.

Loss-of-function mutations of the GPC3 gene are the cause of the human Simpson-Golabi-Behmel syndrome. Based on the overgrowth phenotype of the SimpsonGolabi-Behmel syndrome patients and the key role played by the insulin-like growth factor (IGF) signaling system in regulating embryonic growth, it was speculated that GPC3 regulates IGF signaling. In order to test the validity of this hypothesis, we mated GPC3 knockout mice with insulin receptor substrate-1 (IRS-1) nullizygous mice. We found that GPC3 regulates organism growth independent of IRS-1, suggesting that GPC3 does not modulate IGF signaling. Instead, we found that GPC3 knockout mice exhibit alterations in the Wnt signaling pathway, which is also associated with the regulation of cell proliferation. In particular, the loss of GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling pathway, while concomitantly causing the activation of canonical Wnt/␤-catenin signaling. These in vivo findings were confirmed in vitro upon the ectopic overexpression of GPC3 in mesothelioma cells. In these cells, the GPC3-induced increase in JNK activity was associated with an enhanced response to Wnt5a. Most interestingly, the heparan sulfate chains of GPC3 were not required for its stimulatory activity on Wnt5a signaling and for the formation of GPC3-Wnt5a complexes. We propose that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling, by potentiating non-canonical Wnt signaling, while inhibiting the canonical Wnt signaling pathway.