Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

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How do gravity alterations affect animal and human systems at a cellular/tissue level?

The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: "How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?" This is one of the five major scientific issues of the ESA roadmap "Biology in Space and Analogue Environments". Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects

RET/PTC1-Driven Neoplastic Transformation and Proinvasive Phenotype of Human Thyrocytes Involve Met Induction and β-Catenin Nuclear Translocation1

Activation of the RET gene by chromosomal rearrangements generating RET/PTC oncogenes is a frequent, early, and causative event in papillary thyroid carcinoma (PTC). We have previously shown that, in human primary thyrocytes, RET/PTC1 induces a transcriptional program including the MET proto-oncogene. In PTCs, β-catenin is frequently mislocated to the cytoplasm nucleus. We investigated the interplay between Ret/ptc1 signaling and Met in regulating the proinvasive phenotype and β-catenin localization in cellular models of human PTC. Here, we show that Met protein is expressed and is constitutively active in human thyrocytes exogenously expressing RET/PTC1 as well as a mutant (Y451F) devoid of the main Ret/ptc1 multidocking site. Both in transformed thyrocytes and in the human PTC cell line TPC-1, Ret/ptc1-Y451-dependent signaling and Met cooperated to promote a proinvasive phenotype. Accordingly, gene/functional silencing of either RET/PTC1 or MET abrogated early branching morphogenesis in TPC-1 cells. The same effect was obtained by blocking the common downstream effector Akt. Y451 of Ret/ptc1 was required to promote proliferation and nuclear translocation of β-catenin, suggesting that these oncogene-driven effects are Met-independent. Pharmacologic inhibition of Ret/ptc1 and Met tyrosine kinases by the multitarget small molecule RPI-1 blocked cell proliferation and invasive ability and dislocated β-catenin from the nucleus. Altogether, these results support that Ret/ptc1 cross talks with Met at transcriptional and signaling levels and promotes β-catenin transcriptional activity to drive thyrocyte neoplastic transformation. Such molecular network, promoting disease initiation and acquisition of a proinvasive phenotype, highlights new options to design multitarget therapeutic strategies for PTCs

Integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR signaling loop in papillary thyroid carcinomas.

BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel therapeutic approaches against these tumors. The aim of this study is to identify signaling pathways activated in PTCs. METHODOLOGY/PRINCIPAL FINDINGS: We examined coordinated gene expression patterns of ligand/receptor (L/R) pairs using the L/R database DRLP-rev1 and five publicly available thyroid cancer datasets of gene expression on a total of 41 paired PTC/normal thyroid tissues. We identified 26 (up) and 13 (down) L/R pairs coordinately and differentially expressed. The relevance of these L/R pairs was confirmed by performing the same analysis on REarranged during Transfection (RET)/PTC1-infected thyrocytes with respect to normal thyrocytes. TGFA/EGFR emerged as one of the most tightly regulated L/R pair. Furthermore, PTC clinical samples analyzed by real-time RT-PCR expressed EGFR transcript levels similar to those of 5 normal thyroid tissues from patients with pathologies other than thyroid cancer, whereas significantly elevated levels of TGFA transcripts were only present in PTCs. Biochemical analysis of PTC cell lines demonstrated the presence of EGFR on the cell membrane and TGFA in conditioned media. Moreover, conditioned medium of the PTC cell line NIM-1 activated EGFR expressed on HeLa cells, culminating in both ERK and AKT phosphorylation. In NIM-1 cells harboring BRAF mutation, TGFA stimulated proliferation, contributing to PI3K/AKT activation independent of MEK/ERK signaling. CONCLUSIONS/SIGNIFICANCE: We compiled a reliable list of L/R pairs associated with PTC and validated the biological role of one of the emerged L/R pair, the TGFA/EGFR, in this cancer, in vitro. These data provide a better understanding of the factors involved in the biology of PTCs and would be useful in developing combination therapeutic approaches against these cancers