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Yes / It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reductionmediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a prerequisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator. / The authors would like to thank Cancer Research UK for the post-doctoral fellowship to H.F.Y.

Résumé : La répression fréquente du gène encodant pour le « suppressor of cytokine signaling 1 » (SOCS1) dans le carcinome hépatocellulaire (CHC) et la forte susceptibilité des souris déficientes pour SOCS1 à développer des tumeurs hépatiques expérimentales suggèrent que SOCS joue un rôle de suppresseur de tumeur. Cette notion est supportée par les études impliquant la répression de l’expression de SOCS1 via des évènements épigénétiques ou par les microARN dans plusieurs autres types de cancers. Les mécanismes moléculaires sous-jacents au rôle potentiel de suppresseur de tumeur de SOCS1 dans le foie demeurent à ce jour inconnus. Bien que les récepteurs à activité tyrosine kinase (RTK) sont reconnus pour induire l’expression de l’ARNm de SOCS1, le rôle et les mécanismes par lesquels SOCS1 peut réguler la signalisation des RTK sont incertains. Le RTK MET, qui a pour ligand le facteur de croissance des hépatocytes (HGF), régule plusieurs fonctions cellulaires normales. La dérégulation de la signalisation du récepteur MET joue des rôles importants dans la pathogenèse du CHC. Des études ont démontré que l’activation de MET promeut la prolifération, l’invasion et la migration des cellules cancéreuses du foie ainsi que leur dissémination métastatique. La signalisation aberrante de MET est un trait commun de plusieurs autres cancers et serait à l’origine de l’émergence de la résistance à la chimiothérapie. Dans ce projet, j’ai investigué les mécanismes moléculaires par lesquels SOCS1 régule l’activité du récepteur MET. Mes résultats indiquent que le foie des souris Socs1[indice supérieur -/-]Ifng[indice supérieur -/-] se régénère plus rapidement que celui des souris contrôles. Suivant une stimulation au HGF, les hépatocytes issus des souris Socs1[indice supérieur -/-] Ifng[indice supérieur -/-] présentent une augmentation de la signalisation de MET, de la migration et de la prolifération cellulaires. L’expression exogène de SOCS1 dans différentes lignées cellulaires d’hépatocarcinomes humains et murins inhibe la signalisation induite par HGF. De plus, SOCS1 diminue la prolifération, la croissance indépendante de l’anchrage et la migration dans ces lignées de CHC in cellulo et réduit de façon significative leur croissance dans les essais de xénogreffes chez les souris immunodéficientes. Mes résultats suggèrent que l’activation de la signalisation HGF-MET induit la transcription du gène SOCS1, suivi par une interaction physique entre SOCS1 et MET. L’analyse de divers mutants de SOCS1 révèle que cette interaction implique principalement les domaines SH2 et « kinase inhibitory region » (KIR) de SOCS1. L’activité kinasique de MET est requise pour cette interaction puisque l’interaction entre SOCS1 et un mutant kinase-inactif de MET est fortement réduite. SOCS1 est aussi phosphorylé en aval de MET sur quatre résidus tyrosine (Tyr). Quoique ces résidus Tyr représentent théoriquement des sites d’interaction pour des protéines adaptatrices possédant des domaines de liaison aux phospho-Tyr, elles ne semblent pas impliquées dans l’interaction de SOCS1 avec MET. Je démontre également que SOCS1 induit l’ubiquitination de MET via l’élongation de chaînes de polyubiquitine de type K48, conduisant à sa dégradation par le protéasome. Cette modulation négative de MET par SOCS1 dans les cellules CHC survient indépendamment de la voie de dégradation lysosomale de Cbl qui est partagée par plusieurs autres RTK. // Abstract : Frequent repression of the gene coding for the suppressor of cytokine signaling 1 (SOCS1) in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1 deficient mice to experimental hepatocarcinogenesis suggest a tumor suppressor role for SOCS1. This notion is supported by epigenetic and micro-RNA-mediated blockade of SOCS1 expression in several other cancers. Molecular mechanisms underlying the putative tumor suppressor function of SOCS1 in the liver have not been elucidated yet. Although receptor tyrosine kinases (RTK) can induce SOCS1 mRNA expression, the role and mechanisms of SOCS1 in regulating RTK signaling are not yet clear. c-Met is the RTK for hepatocyte growth factor (HGF) and mediates several normal cellular functions. HGF signaling and MET activation also play important roles in the pathogenesis of HCC. Experimental studies have shown that the activated MET promotes proliferation, invasion and migration of liver cancer cells and enhances metastasis. Aberrant MET signaling is a hallmark of many other cancers and underlies the emergence of chemoresistant clones. In this project, I investigated the molecular mechanisms by which SOCS1 regulates MET RTK activity. My results illustrate that the Socs1[superscript -/-]Ifng[superscript -/-] liver regenerates at a faster rate than the control one. Following HGF stimulation, hepatocytes from Socs1[superscrip -/-]Ifng[superscript -/-] mice display increased MET signaling, cell migration and proliferation. Forced expression of SOCS1 inhibits HGF-induced signaling pathways in different human or murine hepatoma cell lines. Furthermore, SOCS1 also decreases cell proliferation, anchorage-independent growth, and migration of HCC cell lines in cellulo, and results in significant inhibition of their growth as xenografts in immunodeficient mice. My findings show that activation of HGF-MET signaling results in transcriptional activation of SOCS1 gene, followed a physical interaction between SOCS1 and MET. Analysis of various SOCS1 mutants reveals that this interaction is mediated primarily via the SH2 and the kinase inhibitory region (KIR) domain of SOCS1. MET kinase activity is required for this interaction since SOCS1 binding to a kinase-dead MET mutant is dramatically reduced. MET promotes phosphorylation of SOCS1 on four tyrosine (Tyr) residues. Although these Tyr might represent potential binding sites for adaptors containing phospho-Tyr-binding domains, they do not appear to be involved in the interaction of SOCS1 with MET. I also show that SOCS1 induces polyubiquitination of MET via K48-ubiquitin chain elongation leading to its degradation by proteasomes. The SOCS1-mediated downmodulation of MET expression in HCC cells occurs independently of the Cbl-mediated lysosomal degradation pathway shared by many other RTKs. Taken together, my findings show that SOCS1 attenuates HGF-induced cellular functions by targeting the activated MET receptor for proteasomal degradation.

Das Kolonkarzinom ist eine der häufigsten Tumorerkrankungen weltweit. Etwa 50 % der Patienten entwickeln Fernmetastasen. Diese haben eine sehr schlechte Überlebensprognose. Deshalb fokussiert die Forschung auf die Identifizierung neuer, molekularer Marker für eine verbesserte Metastasierungsvorhersage. Identifizierte Hochrisiko-Patienten könnten somit rechtzeitig eine individualisierte, intensivere Therapie erhalten. MACC1 (Metastasis-associated in colon cancer 1) ist ein neu identifiziertes Gen, das in Kolonkarzinomen und deren Fernmetastasen überexprimiert wird. Die Domänenstruktur von MACC1 ist kennzeichnend für Proteine der Rezeptor-Tyrosinkinase-Signalwege. Ziel dieser Arbeit war die Aufklärung der zellulären Funktion von MACC1 und seiner Rolle in der Tumorprogression sowie die Evaluierung von MACC1 als molekularer Metastasierungsmarker. MACC1-überexprimierende Tumorzellen zeigten in Abhängigkeit von der Domänenstruktur in in vitro Assays ein erhöhtes migratorisches, invasives und proliferatives Potential. Der Einfluss von MACC1 auf die Metastasierungskapazität von Tumorzellen konnte auch im Tiermodell belegt werden. Der Hepatocyte-growth-factor (HGF) induziert die epitheliale-mesenchymale Transition MACC1-exprimierender Zellen und die nukleäre Translokation von MACC1. Die Expression des HGF-Rezeptors Met war in diesen Zellen stark erhöht. Reportergen-Studien bestätigten die transkriptionelle Regulation von Met durch MACC1. Die Analyse humaner Kolonkarzinome ergab eine signifikant höhere MACC1 Expression in Primärtumoren mit metachroner Fernmetastasierung. MACC1 ist ein neu identifizierter Regulator des HGF/Met-Signalweges und trägt somit entscheidend zur Determinierung des metastatischen Potentials von Tumorzellen bei. MACC1 hat großes Potential als neuer, prognostischer Marker für die Metastasierung des Kolonkarzinoms und ist ein Kandidatengen als Ziel effektiver, molekularer Interventionsstrategien zur Metastasierungs-Prävention. / Colon cancer is one of the most frequent malignant diseases worldwide. About 50% of the patients develop distant metastasis. These patients have only few therapy options and very poor survival rates. Therefore cancer research focuses on the identification of novel molecular markers to provide a better prognosis of the metastatic risk. Identified high-risk patients would get access to an early, individualized therapy. MACC1 (metastasis associated in colon cancer 1) is a newly identified gene that is overexpressed in colon carcinomas and their distant metastases. The MACC1 domain structure is characteristic for proteins of the receptor tyrosine kinase signalling pathways. Aim of this study was the analysis of the cellular function of MACC1, its role in tumor progression and its evaluation as a molecular, prognostic marker for metastasis. MACC1 overexpressing tumor cells revealed higher migratory, invasive, and proliferative potential in in vitro assays. The impact of MACC1 on the metastatic potential of tumors was also shown in mouse models. The hepatocyte growth factor (HGF) induced epithelial-mesenchymal-transition in MACC1 positive cells and MACC1´s nuclear translocation. Expression of the HGF receptor Met was strongly elevated in these cells. Reporter gene experiments confirmed the transcriptional regulation of Met by MACC1. Analyses in human colon carcinomas showed a significantly higher MACC1 expression in tumors that developed distant metastases. MACC1 is a newly identified regulator of the HGF/Met signalling pathway. It contributes decisively to the metastatic capacity of tumor cells. MACC1 has great potential as new prognostic marker for colon cancer metastasis and is a promising candidate as target for effective, molecular intervention strategies for metastasis prevention.

Os efeitos ambientais negativos da urbanização podem ser mitigados pela presença de espaços verdes dentro e ao redor das cidades. Os elementos mais valiosos de tais áreas são reconhecidamente as árvores. Entretanto, existem também alguns riscos associados com a sua presença, os quais expressam a possibilidade de queda da árvore ou de seus galhos por perda de resistência biomecânica, resultando em perigo de morte e estragos a propriedades, bens e infraestrutura. Nesse sentido, a tomografia de impulso tem se mostrado como uma técnica bastante eficaz em detectar fragilidades biomecânicas no lenho. Considerando ainda que o vento é a principal força dinâmica atuante na copa das árvores, este estudo se propôs a (a) simular o comportamento dos ventos sobre a região do Parque Zoobotânico do Museu Paraense Emílio Goeldi, localizado em Belém-PA, durante quatro eventos de chuvas e ventos fortes usando o ENVI-met, (b) quantificar a perda de resistência biomecânica através da tomografia de impulso em 12 árvores presentes no referido parque e (c) identificar as árvores que possuem um maior risco de queda. Os modelos gerados pelo ENVI-met foram capazes de mostrar zonas de turbulência atuando sobre a copa das árvores tomografadas, e levando em conta a perda de resistência biomecânica, o Guajará foi identificado como apresentando o maior risco de queda entre todas as árvores estudadas. Concluiu-se que o ENVI-met prestou-se perfeitamente para a identificação de zonas de turbulência atuando na copa das árvores. Uma vez conhecidas essas turbulências e considerando a perda de resistência biomecânica acusada pela tomografia, ações de manejo pontuais podem ser propostas e executadas visando diminuir o risco de queda de árvores por ventos fortes em eventos futuros. / Negative environmental effects of urbanization can be mitigated by the presence of green spaces in and around cities. The most valuable elements of such green spaces are considered to be trees. Nonetheless, trees can pose some risks, which encompass the likelihood of mechanical failure of trunk or branches, causing injury to people or damaging buildings and properties. Accordingly, impulse tomography has proven to be a very effective technique in detecting biomechanical weaknesses in the wood. Considering wind as the main dynamic force acting on the tree crown, this study aimed to (a) simulate the behavior of winds over the region of the Goeldi Museum (located in Belém, Pará State, Brazil) during four events of heavy rain and strong winds using the ENVI-met software, (b) quantify the loss of biomechanical resistance for 12 trees located at the Museum and (c) identify trees with high possibility of failure. The models generated by ENVI-met were able to find areas of turbulence influencing the canopy of those trees. Together with the loss of biomechanical resistance, it was possible to identify the Guajará as having the greatest risk of failure among all the analyzed trees. It was concluded that ENVI-met represents a great tool in the identification of turbulence areas that influence trees. Once these areas are identified, and considering the loss of biomechanical resistance given by the impulse tomography, punctual management actions can be proposed and put into action for the sake of reducing risk of failure in future events of strong winds.

Os efeitos ambientais negativos da urbanização podem ser mitigados pela presença de espaços verdes dentro e ao redor das cidades. Os elementos mais valiosos de tais áreas são reconhecidamente as árvores. Entretanto, existem também alguns riscos associados com a sua presença, os quais expressam a possibilidade de queda da árvore ou de seus galhos por perda de resistência biomecânica, resultando em perigo de morte e estragos a propriedades, bens e infraestrutura. Nesse sentido, a tomografia de impulso tem se mostrado como uma técnica bastante eficaz em detectar fragilidades biomecânicas no lenho. Considerando ainda que o vento é a principal força dinâmica atuante na copa das árvores, este estudo se propôs a (a) simular o comportamento dos ventos sobre a região do Parque Zoobotânico do Museu Paraense Emílio Goeldi, localizado em Belém-PA, durante quatro eventos de chuvas e ventos fortes usando o ENVI-met, (b) quantificar a perda de resistência biomecânica através da tomografia de impulso em 12 árvores presentes no referido parque e (c) identificar as árvores que possuem um maior risco de queda. Os modelos gerados pelo ENVI-met foram capazes de mostrar zonas de turbulência atuando sobre a copa das árvores tomografadas, e levando em conta a perda de resistência biomecânica, o Guajará foi identificado como apresentando o maior risco de queda entre todas as árvores estudadas. Concluiu-se que o ENVI-met prestou-se perfeitamente para a identificação de zonas de turbulência atuando na copa das árvores. Uma vez conhecidas essas turbulências e considerando a perda de resistência biomecânica acusada pela tomografia, ações de manejo pontuais podem ser propostas e executadas visando diminuir o risco de queda de árvores por ventos fortes em eventos futuros. / Negative environmental effects of urbanization can be mitigated by the presence of green spaces in and around cities. The most valuable elements of such green spaces are considered to be trees. Nonetheless, trees can pose some risks, which encompass the likelihood of mechanical failure of trunk or branches, causing injury to people or damaging buildings and properties. Accordingly, impulse tomography has proven to be a very effective technique in detecting biomechanical weaknesses in the wood. Considering wind as the main dynamic force acting on the tree crown, this study aimed to (a) simulate the behavior of winds over the region of the Goeldi Museum (located in Belém, Pará State, Brazil) during four events of heavy rain and strong winds using the ENVI-met software, (b) quantify the loss of biomechanical resistance for 12 trees located at the Museum and (c) identify trees with high possibility of failure. The models generated by ENVI-met were able to find areas of turbulence influencing the canopy of those trees. Together with the loss of biomechanical resistance, it was possible to identify the Guajará as having the greatest risk of failure among all the analyzed trees. It was concluded that ENVI-met represents a great tool in the identification of turbulence areas that influence trees. Once these areas are identified, and considering the loss of biomechanical resistance given by the impulse tomography, punctual management actions can be proposed and put into action for the sake of reducing risk of failure in future events of strong winds.

This work deals with ecological design and appraisal of quality of the electronic devices throughout their life cycle. This area known worldwide as Eco-Design, becomes an integral part of all electro technical productions. This work brings out not only conception of the Eco-Design, but also next related areas with the aim to decrease limitation of negative impact on environment. At the end of the work is compared and summarized the ecological evaluation of the concrete product types.

In last decades, the increase of megacities in many regions and particularly in developing countries, contributed to deplete rural landscape enhancing the urbanization impacts. Such urban settlements result in high greenhouse gas emissions and negative energy balances. By gathering millions of people, they develop a complex network of infrastructures, services, housings and factories. Climate impacts of metropolitan areas are universally recognized in the urban heat island (UHI) effect that entails the increase of average night temperatures relative to rural surroundings. New global challenges for urban agendas involve the restraint of urban sprawl, the enhancement of urban density and the mitigation of urban climate changes. Densification strategies had risen as key planning tools to be inserted in the urban development practice. Nevertheless, the integration of compact city pattern into the existing urban structure lead to dense arrangements of urban forms, changes transport models, raises human and energy exchanges, shaping new outdoor environments. In the framework of these transformations, the present work explored the interaction between morphological and climate urban variables in urban lands affected by on-going densification and verticalization processes. An integrated research procedure was developed and applied to a case study in the municipality of São Paulo, characterized by high-rise and low-rise zones under development subjected to a subtropical climate. The proposed procedure integrated field data collections, analysis of database and modeling techniques, addressing multiple scales of analysis. Climate and morphological features were gained by available city database, meteorological stations, Local Climate Zone (LCZ) maps, and further integrated by fieldworks. Numerical models were implemented as interpretation data tools to investigate the physical processes and to build the conceptual model of the interactions between urban morphology and climate. ENVImet and Grasshopper computational codes were used to simulate the existing case study area, as well as to implement numerical experiments (scenarios) in which different densification patterns were tested and compared. The calibration process of the ENVI-met model relied on prior sensitivity tests of input parameters in a smaller domain. Main findings underlined the high-rise buildings shading as the main climate driving force at subtropical latitudes, inducing different microclimates in the outdoor spaces. Compact low-rise areas were found highly affected by high temperatures, low-albedo materials and absence of vegetation. High-rise buildings arrangements were discussed focusing on the effects of buildings heights and spacing variability. Finally, results were summarized in urban design precepts helping climate-sensitive practices and understanding of urban lands in which densification and verticalization processes are in action. Design percepts included suggestions on building height and arrangement, materials and green infrastructure. The importance of a local-scale planning was also highlighted. / Nas últimas décadas, o aumento das megacidades em muitas regiões do mundo e particularmente nos países em desenvolvimento, contribuiu para recuo do ambiente rural, aumentando os impactos da urbanização. Grandes assentamentos urbanos resultam em altas emissões de gases de efeito estufa e balanços energéticos negativos. Ao reunir milhões de pessoas, as cidades contemporâneas desenvolvem uma complexa rede de infraestruturas, serviços, moradias e centros produtivos. Os impactos climáticos relacionados são universalmente reconhecidos no efeito de ilha de calor urbana (ICU), que implica o aumento das temperaturas médias noturnas em relação ao entorno rural. Novos desafios globais para as agendas urbanas envolvem a contenção da expansão urbana, o aumento da densidade populacional e a mitigação das mudanças climáticas. Assim, estratégias de densificação surgiram como ferramentas-chave de planejamento a serem inseridas na prática urbana. No entanto, a integração do padrão de cidade compacta na estrutura urbana existente leva a arranjos densos de formas urbanas, requerendo modificações nos modelos de transporte, aumenta as trocas de pessoas e de energia, moldando novos ambientes externos. No âmbito dessas transformações, o presente trabalho explorou a interação entre variáveis urbanas morfológicas e climáticas em áreas urbanas afetadas por processos de densificação e verticalização presentes e futuros. Um procedimento integrado de pesquisa foi desenvolvido e aplicado a um estudo de caso no município de São Paulo, caracterizado por zonas de grande e baixa altura em desenvolvimento, sujeitas a um clima subtropical. O procedimento proposto integrou coletas de campo, análise de conjuntos de dados e técnicas de modelagem, abordando múltiplas escalas de análise. Aspectos climáticos e morfológicos foram obtidos por meio de database disponibilizados pela Prefeitura, estações meteorológicas, mapas de Zonas Climáticas Locais (LCZs) e posteriormente integrados por trabalhos de campo. Modelos numéricos foram implementados como ferramentas de interpretação de dados para investigar os processos físicos e construir o modelo conceitual das interações entre morfologia urbana e clima. Os códigos computacionais ENVI-met e Grasshopper foram usados para simular a área de estudo, bem como para implementar experimentos numéricos (cenários) nos quais diferentes padrões de densificação foram testados e comparados. O processo de calibração do modelo ENVI-met baseou-se em testes de sensibilidade prévios, realizados sobre parâmetros de input em um domínio menor. Os principais resultados ressaltaram o sombreamento causado por grandes objetos construídos como a principal forçante climática nas cidades de latitude subtropical, induzindo diferentes microclimas nos espaços externos ao redor. Tecidos urbanos baixos e compactos foram encontrados afetados por altas temperaturas, materiais de baixo albedo e ausência de vegetação. Arranjos de edifícios altos foram investigados focando nos efeitos das alturas dos edifícios e na variabilidade do espaçamento entre eles. Por fim, os resultados foram resumidos em preceitos de desenho urbano que suportassem uma abordagem de projeto mais sensível ao clima, assim como a compreensão das áreas da cidade onde os processos de densificação e verticalização encontram-se ativos. Os preceitos de desenho urbano incluíam sugestões sobre a altura e disposição dos edifícios, materiais e infraestrutura verde. A importância de um planejamento em escala local também foi destacada.

Le récepteur à activité tyrosine kinase MET et son ligand le facteur de croissance des hepatocytes (Hepatocyte Growth Factor/Scattor Factor (HGF/SF)) sont essentiels pour la migration, la morphogenèse et la survie des cellules épithéliales. En plus de son implication et son importance physiologiques, la dérégulation de la signalisation de MET favorise la progression et l’invasion tumorales dans plusieurs types de cancers. Au sein des tumeurs, l’hypoxie est également un phénomène crucial qui induit une réponse adaptative menant à l’invasion, la métastase cancéreuses et la résistance aux traitements.Nous avons démontré que dans des conditions hypoxiques, la phosphorylation de MET induite par sa liaison au ligand, des mutations activatrices ou sa surexpression, est diminuée de manière importante in vitro et in vivo dans des modèles de tumeurs expérimentales chez la souris. Cette baisse de phosphorylation est très rapide et est réversible quand les cellules sont replacées en normoxie. Alors que la phosphorylation de GAB1, principal partenaire de MET, est également diminuée en hypoxie, l’activation des voies de signalisation en aval AKT et ERK n’est pas affectée et reste bien dépendante de l’activité du récepteur et du recrutement de GAB1. De la même façon, l’HGF/SF induit des réponses de motilité, de dispersion, de morphogenèse et de survie similaires en normoxie et en hypoxie. De manière intéressante, le traitement par deux inhibiteurs de tyrosine kinase (ITK) ciblant MET (PHA-665752 et SU11274) est moins efficace en hypoxie pour inhiber les voies de signalisation AKT et ERK ainsi les réponses cellulaires induites par MET. Comme pour la phosphorylation de MET, la résistance à ces ITK est un phénomène réversible. Ainsi, alors que l’hypoxie n’affecte pas les voies de signalisation en aval ni les effets biologiques, elle diminue la sensibilité de MET aux ITK induisant donc une résistance immédiate. L’ensemble de ces données pourrait fournir de nouvelles perspectives dans l’utilisation des thérapies ciblant MET dans les tumeurs solides. / The receptor tyrosine kinase MET and its ligand the Hepatocyte Growth Factor/Scattor Factor (HGF/SF) are essential for migration, morphogenesis and survival of epithelial cells. Beside its physiological involvement, deregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Inside the tumors, hypoxia is also a crucial phenomenon promoting an adaptive response able to induce invasion, metastasis and resistance to treatment.We show that under hypoxia, MET phosphorylation induced by ligand-stimulation, activating mutation or overexpression, is drastically decreased both in cell culture and in experimental tumors. This decrease in MET phosphorylation occurs within minutes and is reversible when cells are returned to normoxia. While phosphorylation of the proximal signaling adaptor GAB1 is also decreased in hypoxia, activation of the downstream kinases ERK and AKT is not affected, but is still dependent on MET receptor activity. Consistently, several cellular responses induced by HGF/SF, including motility, morphogenesis or survival, are still efficiently induced. Interestingly, treatment with two tyrosine kinase inhibitors targeting MET (PHA-665752 and SU11274) are less efficient to inhibit the downstream kinases ERK and AKT and cellular responses induced by MET in hypoxia compared to normoxia. Similarly to MET phosphorylation, this resistance to TKI is a reversible phenomenon. Therefore, while hypoxia does not affect downstream signaling and cellular responses, it decreases MET sensitivity to TKIs targeting the receptor thus providing an immediate resistance. This may provide new insights in the use of MET targeted therapies in solid tumors.