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Signal transduction of the RET receptor tyrosine kinase is involved in developmental processes as well as in neoplastic transformation. Activation of RET initiates receptor autophosphorylation on specific tyrosines that act as docking sites for downstream signaling molecules. Using the cytoplasmatic part of RET as bait in a yeast two-hybrid screen, we identified a novel SH2 and SH3 domain containing adaptor protein previously termed Grap-2/Grf40/GrpL/GRID and its murine homologue as Gads/Mona, respectively. This protein, predominantly expressed in cells of hematopoietic origin, is involved in signaling downstream of the T-cell receptor and the receptor for monocyte colony-stimulating factor. Here, we show that Grap-2 is also expressed in neuroendocrine tumors and cell lines known to bear mutated forms of RET. Endogenously expressed RET and Grap-2 coimmunoprecipitate from lysates of a medullary thyroid carcinoma cell line. Grap-2 directly associates with RET in pull-down experiments using in vitro translated proteins. Overexpression of Grap-2 inhibits RET-induced NF-jB activation, and cotransfection of Grap-2 significantly reduces focus formation induced by oncogenic RET in NIH 3T3 cells. Taken together, these results suggest that besides being involved in tyrosine kinase signaling in hematopoietic cells, Grap-2 plays a tissue-specific role as an inhibitor of RET mitogenic signaling.

Abstract.Multiple endocrine neoplasia type 1(MEN1) is a human hereditary tumor syndrome characterized by the development of endocrine adenomas of the parathyroid, anterior pituitary, and enteropancreatic tissue. Several lines of evidence have implicated the recently identified MENI gene located on chromosome 11813 as a recessive tumor suppressor gene. Here, we analyzed MENI wild-type gene expression in tumors from a large MEN1 kindred. A deletion of codons 227-228 (678de16) located in exon 4 was found in tumor and peripheral blood complementary DNA using a simplified single-strand conformational polymorphism (SSCP) approach well suited for clinical MENI mutation screening. The identified 678de16 cDNA mutation deletes a potential phosphorylation site (Tyr227) and corresponds to a germ line mutation co-segregating with disease phenotype in this MENI family. Loss of heterozygosity analysis by fluorescent microsatellite PCR showed an exclusive loss of the MEN1 wild-type (and retention of the mutated) allele detectable in DNA from microdissected parathyroid and pancreatic, but not in adrenal, adenomas.Our findings confirm the synergism between MENI gene mutations and subsequent MENI allelic losses in the tumorigenesis of MEN1-associated adenomas.

IntroductionSchool meal programs operate throughout Africa, serving as a social safety net and aiming to improve children's nutrition, influence their dietary choices, and strengthen the agrifood economy through local procurement. Despite their rapid expansion in the past decade, there has been no systematic effort to comprehensively document school feeding activities across the continent.MethodsDetailed information on school feeding activities in each country was captured in the Global Survey of School Meal Programs©, which launched in 2019. An invitation to participate was extended to each government, which appointed a national-level respondent to gather information on every large-scale school meal program in the country.ResultsForty-one countries in Africa (38 in sub-Saharan Africa) responded to the survey in 2019 with information on 68 large-scale programs that together reached 60.1 million children. Across these countries, the aggregate school feeding budget was USD 1.3 billion. Diversity in school meal programs is evident across regions, country income levels, and levels of national commitment. Coverage rates tended to be highest in southern Africa, in countries with school feeding as a line item in the national budget, and in countries with the greatest domestic share of the school feeding budget. Diversity in the school menu tended to be greatest in programs that sourced food through domestic purchase rather than relying on foreign in-kind donations. To address micronutrient malnutrition, about two-thirds of the programs served fortified foods, and one-quarter included micronutrient supplements. Even as rates of overweight/obesity are rising among African school children, just 10% of school meal programs identified its prevention as an objective.ConclusionThe extent to which school meal programs in Africa are supported with domestic funding reflects a dramatic shift in favor of national ownership and domestic food procurement. At the same time, programs have grappled with inadequate and unpredictable budgets and challenges related to supply chains and logistics—impediments that need to be addressed if these programs are to achieve their objectives. Overall, the survey results underscore the important position of school meal programs within African food systems and their potential (if well-designed) to sustainably improve food security, child health, and nutrition.

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