RESUMO
Progression of solid tumors to the metastatic stage is accountable for the majority of cancer-related deaths. Further understanding of the molecular mechanisms governing metastasis is essential for the development of antimetastatic regimens. Here, we aimed to identify Rac activators that could promote metastasis downstream of human epithelial growth factor receptor 2 (HER2). We investigated if Dedicator of Cytokinesis 1 (DOCK1), based on its evolutionarily conserved role in receptor tyrosine kinases (RTKs)-mediated Rac activation and cell invasion, could be a regulator of metastasis. We report that high expression of DOCK1 in HER2(+) and basal breast cancer subtypes inversely correlates with human patients' survival. Mechanistically, DOCK1 interacts with HER2 and promotes HER2-induced Rac activation and cell migration. To gain further insight, we developed a HER2 breast cancer mouse model with mammary-gland-specific inactivation of DOCK1. In this in vivo model, a significant decrease in tumor growth and metastasis in lungs was found in animals where DOCK1 is inactivated. Furthermore, we found that DOCK1 is required for maximal activation of two HER2 effectors, c-JUN and STAT3. Using an unbiased gene profiling approach, we identified a mammary tumor DOCK1-associated gene signature enriched for genes implicated in response to IFN type I. This analysis revealed a unique set of genes, including Receptor Transporter Protein 4 (RTP4) and STAT1, for which the expression levels can be used to independently predict breast cancer outcome in HER2(+) patients. Our work demonstrates DOCK1-Rac signaling as an HER2 effector pathway essential for HER2-mediated breast cancer progression to metastasis and offers a therapeutic opportunity to limit the spread of metastatic breast cancers.
Assuntos
Neoplasias da Mama/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Pulmonares/secundário , Receptor ErbB-2/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neuregulina-1/metabolismo , Prognóstico , Resultado do Tratamento , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Nuclear translocation, driven by the motility apparatus consisting of the cytoplasmic dynein motor and microtubules, is essential for cell migration during embryonic development. Bicaudal-D (Bic-D), an evolutionarily conserved dynein-interacting protein, is required for developmental control of nuclear migration in Drosophila. Nothing is known about the signaling events that coordinate the function of Bic-D and dynein during development. Here, we show that Misshapen (Msn), the fly homolog of the vertebrate Nck-interacting kinase is a component of a novel signaling pathway that regulates photoreceptor (R-cell) nuclear migration in the developing Drosophila compound eye. Msn, like Bic-D, is required for the apical migration of differentiating R-cell precursor nuclei. msn displays strong genetic interaction with Bic-D. Biochemical studies demonstrate that Msn increases the phosphorylation of Bic-D, which appears to be necessary for the apical accumulation of both Bic-D and dynein in developing R-cell precursor cells. We propose that Msn functions together with Bic-D to regulate the apical localization of dynein in generating directed nuclear migration within differentiating R-cell precursor cells.
Assuntos
Movimento Celular/genética , Proteínas de Drosophila/genética , Drosophila/genética , Dineínas/genética , Olho/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Serina-Treonina Quinases/genética , Animais , Núcleo Celular , Drosophila/anatomia & histologia , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Dineínas/metabolismo , Fosforilação , Células Fotorreceptoras/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The establishment of tissue architecture in the nervous system requires the proper migration and positioning of newly born neurons during embryonic development. Defects in nuclear translocation, a key process in neuronal positioning, are associated with brain diseases such as lissencephaly in humans. Accumulated evidence suggests that the molecular mechanisms controlling neuronal movement are conserved throughout evolution. While the initial events of neuronal migration have been extensively studied, less is known about the molecular details underlying the establishment of neuronal architecture after initial migration. RESULTS: In a search for novel players in the control of photoreceptor (R cell) positioning in the developing fly visual system, we found that misexpression of the RabGAP RN-Tre disrupted the apical localization of R-cell nuclei. RN-Tre interacts with Rab5 and Rab11 in the fly eye. Genetic analysis shows that Rab5, Shi and Rab11 are required for maintaining apical localization of R-cell nuclei. CONCLUSIONS: We propose that Rab5, Shi and Rab11 function together in a vesicular transport pathway for regulating R-cell positioning in the developing eye.