RhoGEFs in Cell Motility: Novel Links Between Rgnef and Focal Adhesion Kinase

Rho guanine exchange factors (GEFs) are a large, diverse family of proteins defined by their ability to catalyze the exchange of GDP for GTP on small GTPase proteins such as Rho family members. GEFs act as integrators from varied intra- and extracellular sources to promote spatiotemporal activity of Rho GTPases that control signaling pathways regulating cell proliferation and movement. Here we review recent studies elucidating roles of RhoGEF proteins in cell motility. Emphasis is placed on Dbl-family GEFs and connections to development, integrin signaling to Rho GTPases regulating cell adhesion and movement, and how these signals may enhance tumor progression. Moreover, RhoGEFs have additional domains that confer distinctive functions or specificity. We will focus on a unique interaction between Rgnef (also termed Arhgef28 or p190RhoGEF) and focal adhesion kinase (FAK), a non-receptor tyrosine kinase that controls migration properties of normal and tumor cells. This Rgnef-FAK interaction activates canonical GEF-dependent RhoA GTPase activity to govern contractility and also functions as a scaffold in a GEF-independent manner to enhance FAK activation. Recent studies have also brought to light the importance of specific regions within the Rgnef pleckstrin homology (PH) domain for targeting the membrane. As revealed by ongoing Rgnef-FAK investigations, exploring GEF roles in cancer will yield fundamental new information on the molecular mechanisms promoting tumor spread and metastasis

Regulation of Focal Adhesion Kinase by a Novel Protein Inhibitor FIP200

Focal adhesion kinase (FAK) is a major mediator of integrin signaling pathways. The mechanisms of regulation of FAK activity and its associated cellular functions are not very well understood. Here, we present data suggesting that a novel protein FIP200 functions as an inhibitor for FAK. We show the association of endogenous FIP200 with FAK, which is decreased upon integrin-mediated cell adhesion concomitant with FAK activation. In vitro- and in vivo-binding studies indicate that FIP200 interacts with FAK through multiple domains directly. FIP200 bound to the kinase domain of FAK inhibited its kinase activity in vitro and its autophosphorylation in vivo. Overexpression of FIP200 or its segments inhibited cell spreading, cell migration, and cell cycle progression, which correlated with their inhibition of FAK activity in vivo. The inhibition of these cellular functions by FIP200 could be rescued by coexpression of FAK. Last, we show that disruption of the functional interaction between endogenous FIP200 with FAK leads to increased FAK phosphorylation and partial restoration of cell cycle progression in cells plated on poly-l-lysine, providing further support for FIP200 as a negative regulator of FAK. Together, these results identify FIP200 as a novel protein inhibitor for FAK

Acesso a ambulatório pediátrico de um hospital universitário Evaluation of access to the pediatric service of a university hospital

INTRODUÇÃO: No Brasil verifica-se um descompasso entre o aumento das necessidades de atenção à saúde e de sua oferta. O Sistema Único de Saúde, cujas deretrizes preconizam a atenção universal e eqüânime, determina a relevância desta temática dentro do campo da avaliação dos serviços de saúde. Assim, foram estudados dois ambulatórios de pediatria de um hospital universitário, um geral e outro de uma subespecialiadade (pneumologia), comparando os usuários quanto ao acesso. MÉTODO: Foram aplicados 221 questionários entre clientes de ambos os ambulatórios de pediatria com o objetivo de se estudar e comparar variáveis socioeconômicas, procedência, acesso aos referidos ambulatórios e outros serviços de saúde. RESULTADOS: Evidenciou-se grande dificuldade de locomoção dos pacientes, a maioria dos quais são encaminhados por serviços de saúde locais. Dos pacientes atendidos 40% não receberam nenhum atendimento anteriormente à sua chegada ao hospital, fato que decorre principalmente de seu baixo nível socioeconômico, que os torna dependentes exclusivamente dos serviços públicos de saúde. A comparação entre os dois ambulatórios mostra que os pacientes do ambulatório de especialidade têm melhor nível socioeconômico e são menos dependentes dos serviços públicos, configurando desta forma uma situação de ineqüidade. CONCLUSÕES: É apontado o melhor nível socioeconômico dos usuários da especialidade bem como questões organizacionais do próprio serviço como os responsáveis pela iniqüidade verificada.<br>INTRODUCTION: In Brazil, one can verify an imbalance between the increase in the need for health care and its supply. The consolidation of the National Health System which recommends universality and equity in care, makes this issue important in the field of health service evaluation. Two pediatric services in a university hospital, one general and the other specialized are studied and compared in terms of their clients' access. METHOD: Questionnaires were applied to 221 users of the general pediatrics outpatient departments of one of the specialities with a view to studying and comparing socioeconomic and several other variables related to the access to these and other health services. RESULTS: A high level of difficulty in the users' locomotion from local health services to the hospital was noted.Of the patients attended, 40% did not receive any kind of care before their arrival and were dependent exclusively on State-run health services. The clients of the speciality were different as regards several variables when compared to the users of the general outpatients' department. The fact that they are at a better socioeconomic level and are less dependent on State-run services brings out the social inequalities involved. CONCLUSION: Socioeconomic conditions, as well as organizational aspects of the service, are seen to be both causes and consequences of social inequalitiy verified