We describe the identification and characterization of a novel gene, sur-8, that positively regulates Ras-mediated signal transduction during C. elegans vulval development. Reduction of sur-8 function suppresses an activated ras mutation and dramatically enhances phenotypes of mpk-1 MAP kinase and ksr-1 mutations, while increase of sur-8 dosage enhances an activated ras mutation. sur-8 appears to act downstream of or in parallel to ras but upstream of raf. sur-8 encodes a conserved protein that is composed predominantly of leucine-rich repeats. The SUR-8 protein interacts directly with Ras but not with the Ras(P34G) mutant protein, suggesting that SUR-8 may mediate its effects through Ras binding. A structural and functional SUR-8 homolog in humans specifically binds K-Ras and N-Ras but not H-Ras in vitro.

Protein tyrosine phosphatase receptor-type T (PTPRT) is the most frequently mutated tyrosine phosphatase in human cancers. However, the cell signaling pathways regulated by PTPRT largely remain to be elucidated. Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth, fail to form xenograft tumors in nude mice, and have decreased phosphorylation of p130CAS, SHP2, and AKT. PTPRT knockout mice that we generated exhibit increased levels of colonic paxillin phosphorylation at residue Y88 and are highly susceptible to carcinogen azoxymethane-induced colon tumor, providing critical in vivo evidence that PTPRT normally functions as a tumor suppressor. Moreover, similarly increased paxillin pY88 is also found as a common feature of human colon cancers. These studies reveal an important signaling pathway that plays a critical role in colorectal tumorigenesis.colorectal cancer R eversible tyrosine phosphorylation, which is coordinately controlled by protein tyrosine kinases (PTKs) and phosphatases (PTPs), governs numerous signaling pathways that regulate cell proliferation, apoptosis, adhesion, and migration. Over the last two decades, many PTKs have been found to be mutated in a variety of different tumor types (reviewed in ref. 1). In contrast to PTKs, the role of PTPs in tumorigenesis is underexplored. To systematically evaluate possible roles of PTPs in tumorigenesis, we used a high throughput molecular and bioinformatics approach to detect genetic alterations of the tyrosine phosphatase gene family in colorectal cancers (CRCs) (2). Among the six mutated PTPs that we identified, protein tyrosine phosphatase receptor-type T (PTPRT), also known as PTPρ, was the most frequently mutated (2). In addition, we and others found that PTPRT is also mutated in lung, stomach, and skin cancers (2, 3). The spectrum of mutations, which includes nonsense mutations and frameshifts, suggested that these mutations were inactivating (2). Biochemical analyses demonstrated that missense mutations in the catalytic domains of PTPRT diminished its phosphatase activity, whereas overexpression of PTPRT inhibited CRC cell growth (2). Taken together, these studies suggest that PTPRT normally acts as a tumor suppressor gene. In light of these data, it is important to identify the functionally significant substrates of PTPRT as well as to elucidate the signal transduction pathways regulated by this phosphatase. Here, we report that paxillin, an adaptor protein involved in cell adhesion, migration, proliferation, and apoptosis (4, 5), is a direct substrate of PTPRT and that phospho-paxillin has oncogenic properties. We further demonstrate that in an in vivo model, PTPRT is both a potent tumor suppressor gene and a key regulator of colonic ph...

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Native American grape (Vitis) species have many desirable properties for winegrape breeding, but hybrids of these non-vinifera wild grapes with Vitis vinifera often have undesirable aromas. Other than the foxy-smelling compounds in Vitis labrusca and Vitis rotundifolia , the aromas inherent to American Vitis species are not well characterized. In this paper, the key odorants in wine produced from the American grape species Vitis riparia and Vitis cinerea were characterized in comparison to wine produced from European winegrapes (V. vinifera). Volatile compounds were extracted by solid-phase microextraction (SPME) and identified by gas chromatography-olfactometry/mass spectrometry (GC-O/MS). On the basis of flavor dilution values, most grape-derived compounds with fruity and floral aromas were at similar potency, but non-vinifera wines had higher concentrations of odorants with vegetative and earthy aromas: eugenol, cis-3-hexenol, 1,8-cineole, 3-isobutyl-2-methoxypyrazine (IBMP), and 3-isopropyl-2-methoxypyrazine (IPMP). Elevated concentrations of these compounds in non-vinifera wines were confirmed by quantitative GC-MS. Concentrations of IBMP and IPMP were well above sensory threshold in both non-vinifera wines. In a follow-up study, IBMP and IPMP were surveyed in 31 accessions of V. riparia, V. rupestris, and V. cinerea. Some accessions had concentrations of >350 pg/g IBMP or >30 pg/g IPMP, well above concentrations reported in previous studies of harvest-ripe vinifera grapes. Methyl anthranilate and 2-aminoacetophenone, key odorants responsible for the foxiness of V. labrusca grapes, were undetectable in both the V. riparia and V. cinerea wines (<10 μg/L).

The treatments had variable impacts on wine anthocyanin, berry skin tannin, berry seed tannin, and wine tannin depending on year. Wine tannin (42 to 64 mg/L) and tannin extractability (5 to 6%) were both very low compared to values typically observed in red wines produced from V. vinifera. Using a two-alternative forced choice test, panelists reported ST+CL wines were fruitier than the control and ST wines and that ST wines were less fruity than the control in both years. An economic analysis indicated that in order for growers/wineries to maintain their economic welfare, bottle prices would have to increase by $0.02 to $0.41 depending on the practice and year to compensate for additional labor costs and lost yield in implementing these crop-load management practices.