102 research outputs found
Paper determinant de l'activitat LRRK2 en la malaltia de Parkinson
No full textTreballs Finals de Grau de Farmàcia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 2024. Tutor/a: Francesc Tebar RamonLa malaltia de Parkinson (MP) és una malaltia neurodegenerativa que afecta a milions
de persones i per la que, de moment, no existeix cap tractament que freni l’avanç.
Aquesta malaltia es caracteritza per la mort de les neurones dopaminèrgiques de la
substantia nigra, cosa que comporta l’aparició de tremolors, rigidesa i bradicinèsia, entre
altres símptomes.
La cinasa LRRK2 sol ser una de les principals causes genètiques d’aquesta malaltia
degut a que pot contenir certes mutacions que donen lloc a una forma de MP hereditària.
Tot i així, s’ha pogut observar com en absència d’aquestes mutacions que incrementen
el risc de patir MP, aquesta cinasa podria estar implicada en l’avanç i la propagació de
la malaltia. Aquest descobriment obre les portes a nous tractaments de la malaltia amb
LRRK2 com a diana. Tant els tractaments farmacològics proposats, com les teràpies
gèniques son molt prometedors, però encara és molt aviat per assegurar que son
tractaments efectius i segurs. A més, cada tipus de tractament te les seves fortaleses i
els seus defectes, i ara per ara no es pot assegurar un benefici diferencial entre ells.
Finalment, cal entendre que en tractar-se d’un camp d’estudi molt innovador, la
informació obtinguda que prové d’estudis in vitro amb cultius cel·lulars i in vivo en models
animals, com el ratolí, s’haurà de validar en humans
Rac1 y Calmodulina regulan la dinámica de membrana durante la endocitosis independiente de Clatrina
No full textEl fosfolípido PI(4,5)P2 ha sido descrito ampliamente como un factor clave en la endocitosis. De hecho, numerosas proteínas endocíticas contienen dominios de unión específicos para PI(4,5)P2. La dinámica de su metabolismo está finamente regulada por diversos enzimas que pueden fosforilarlo, defosforilarlo, hidrolizarlo o sintetizarlo a partir de precursores, cambiando su concentración en dominios específicos de la membrana. En los primeros pasos de la endocitosis, la concentración de PI(4,5)P2 aumenta y recluta clatrina u otros tipos de proteínas de cubierta o asociadas a procesos de remodelación de membrana, dando lugar a una invaginación. Más tarde, los niveles de PI(4,5)P2 deben reducirse para completar el proceso de formación de vesículas.
En los últimos años, nuestro grupo ha descrito como la calmodulina (CaM) está regulando la interacción entre Rac1 y PIP5K, el principal enzima productor de PI(4,5)P2. La inhibición de la CaM, que es el sensor de calcio (Ca2+) más importante en células no musculares, induce la formación de invaginaciones tubulares ricas en PI(4,5)P2 provenientes de la membrana plasmática, que parecen formar parte de un proceso endocítico independiente de clatrina. Sin embargo, también se observó que la sobreexpresión del Rac1 constitutivamente activo (Rac1G12V) inhibe las tubulaciones inducidas por la inhibición de CaM, lo que podría deberse a la acción de efectores de Rac1 relacionados con el metabolismo de PI(4,5)P2, como la fosfolipasa C (PLC), o relacionados con la dinámica del citoesqueleto. Durante esta tesis, hemos demostrado el requerimiento de PI(4,5)P2 en la formación de los túbulos endocíticos, y hemos descrito como la CaM puede estar regulando sus niveles a través de la regulación de Rac1 y posiblemente de PKC, específicamente en las balsas lipídicas, donde se producen la mayoría de procesos endocíticos independientes de clatrina.
La dinámica de las adhesiones focales, que vinculan el citoesqueleto con la matriz extracelular a través de la integrina, está también regulada por la endocitosis durante la migración celular. Existe además una estrecha regulación recíproca entre las RhoGTPasas y el tráfico de integrinas, que se extiende a lo largo del eje anteroposterior de la célula en migración, en el que generalmente Rac1 está activado en la parte anterior, y RhoA en la parte posterior. Los análisis de internalización realizados nos han permitido descubrir que las tubulaciones inducidas por PI(4,5)P2 son una vía de entrada de beta1-integrina, que aceleran su internalización y la excluyen de los compartimentos endosomales tempranos, impidiendo posiblemente un reciclaje rápido hacia la membrana plasmática. La activación constitutiva de Rac1 impide esta entrada rápida a través de los túbulos.
Los sitios de endocitosis están estrechamente ligados al citoesqueleto de actina, ya que éste puede contribuir a la deformación, invaginación o rotura de la membrana. La cortactina modula la dinámica del citoesqueleto de actina durante la CDE y la CIE, en asociación con diversas proteínas como WASP, dinamina o Arp2/3. Se sabe que la cortactina requiere de Rac1 para ser translocada a la membrana plasmática pero no se conoce bien el mecanismo. Asimismo, la tensión de la membrana plasmática es también un elemento clave en la regulación de la internalización, estimulándose la endocitosis en regiones con una baja tensión de membrana. La miosina, en especial la miosina II de células no musculares, es, junto con la actina, uno de los principales reguladores de la tensión de membrana, especialmente durante la migración celular. El estudio de la función de cortactina y miosina permitió demostrar que la actividad de Rac1 regula negativamente la formación de las invaginaciones tubulares inducidas por PI(4,5)P2. Hemos demostrado que la acción de POR1, un efector conocido de Rac1, media la translocación de cortactina a la membrana plasmática. Además, se ha descrito por vez primera una activación
directa de ROCK1 por parte de Rac1, que pemite la activación de la miosina y su asociación con el citoesqueleto de actina, lo cual es necesario para la inhibición de las tubulaciones por Rac1 activo.It has been described that specific calmodulin inhibition, W13-treatment, increased the percentage of cells with tubular plasma membrane structures, which corresponds to the Arf6-dependent and clathrin-independent endocytosis pathway. The present thesis shows that these tubular transport membranes by which β1-integrin is endocytosed, depends on the increased PI(4,5)P2 levels in lipid rafts, dynamin and dynein motor proteins. As for W13, exogenous PI(4,5)P2 or PIP5K expression generated-tubules are inhibited by expression of the active Rac1 mutant (Rac1-G12V). Therefore, the molecular mechanisms downstream of Rac1 that controls such tubules formation have been analyzed biochemically and by the expression of different Rac1 mutants. The results indicate that PLC and ROCK1, possibly in combination with POR1, are the main Rac1 effectors to impede plasma membrane invagination, by decreasing the PI(4,5)P2 levels and promoting cortical actomyosin, respectively. Importantly, among the interplay of proteins that participates in membrane remodeling, this study reveals for the first time that the well-known downstream RhoA effector ROCK1 acts as an important effector of Rac1 to regulate actin-myosin at the cell cortex. This study provides new insights in the mode of Rac1 action on plasma membrane dynamics regulation
Role of calmodulin in the modulation of the MAPK signalling pathway and the transactivation of epidermal growth factor receptor mediated by PKC
No full textAbstractWe have recently shown that calmodulin (CaM) regulates the trafficking of epidermal growth factor receptor (EGFR) as well as the mitogen-activated protein kinase (MAPK) signalling pathway. However, the overall regulation of the MAPK pathway is achieved through a complex interplay of other several upstream effectors including G-proteins, EGF, EGFR, protein kinase C (PKC), phosphatidylinositol-3-kinase and CaM. In order to understand the role of CaM in the PKC-mediated transactivation of EGFR we have analysed the effect of a CaM antagonist, N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide, on the 12-O-tetradecanoylphorbol-13-acetate-mediated activation of EGFR and the subsequent MAPK activation. The results show that CaM interferes with MAPK activation and the transactivation of EGFR mediated by PKC
Hijos de su tiempo. Los sacerdotes obreros de Tarragona. Mundo obrero, antifranquismo y represión (1951-1977)
No full textAquesta tesi doctoral analitza el fenomen dels sacerdots i religiosos obrers a Reus i Tarragona entre els anys 1951 i 1977, destacant la seva gènesi, trajectòria, inquietuds i aspiracions en el marc de la dictadura franquista, aliada formalment amb l’Església catòlica espanyola. Per a la reconstrucció d’aquest fet històric s’ha examinat el contrast que els futurs sacerdots obrers van viure entre l’educació rebuda als seminaris i centres eclesiàstics als quals es van formar, i l’experiència que van tenir posteriorment a les seves parròquies, als barris obrers on van residir, a les fàbriques o tallers on van treballar o a les relacions humanes sorgides dels diferents ambients als quals van ser-hi. Les esperances de renovació que va generar el Concili Vaticà II (1962-1965) a nivell universal i el context europeu de gran ebullició i aires de canvi amb el Maig del 68, l’auge del moviment juvenil i estudiantil i el propi context espanyol, van marcar una generació de seminaristes que van començar a mostrar inquietuds socials.
Per a contextualitzar l’experiència vital dels sacerdots i religiosos obrers als barris perifèrics de Reus i Tarragona, s’han estudiat els col•lectius, grups i persones individuals amb qui van compartir la seva vocació de proximitat al món obrer i van teixir xarxes de relació humana, solidaritat, pensament, denúncia i acció contra el règim franquista: altres sacerdots amb diversos compromisos, les missioneres de l’Institut de Missioneres Seculars i els militants de l’apostolat seglar. Finalment, s’examinen els diferents tipus i graus de repressió de l’Estat franquista que van patir els sacerdots obrers i conciliars a causa de la seva tasca de protecció i cobertura a la militància política i sindical durant la clandestinitat, a més de la seva participació com a ciutadans comuns a les protestes antifranquistes i les reivindicacions de serveis bàsics als barris obrers de Reus i Tarragona.Esta tesis doctoral analiza el fenómeno de los sacerdotes y religiosos obreros en Reus y Tarragona entre los años 1951 y 1977, destacando su génesis, trayectoria, inquietudes y aspiraciones en el marco de la dictadura franquista, aliada formalmente con la Iglesia católica española. Para la reconstrucción de este hecho histórico se ha examinado el contraste que los futuros sacerdotes obreros vivieron entre la educación recibida en los seminarios y centros eclesiásticos en los que se formaron, y la experiencia que tuvieron posteriormente en sus respectivas parroquias, en los barrios obreros en los que residieron, en las fábricas o talleres en los que trabajaron o en las relaciones humanas surgidas de los distintos ambientes en los que se desenvolvieron. Las esperanzas de renovación que generó el Concilio Vaticano II (1962-1965) a nivel universal y el contexto europeo de gran ebullición y aires de cambio con el Mayo del 68, el auge del movimiento juvenil y estudiantil y el propio contexto español, marcaron una generación de seminaristas que empezaron a mostrar inquietudes sociales.
Para contextualizar la experiencia vital de los sacerdotes y religiosos obreros en los barrios periféricos de Reus y Tarragona, se han estudiado los colectivos, grupos y personas individuales con quienes compartieron su vocación de proximidad al mundo obrero y tejieron redes de relación humana, solidaridad, pensamiento, denuncia y acción contra el régimen franquista: otros sacerdotes con distintos compromisos, las misioneras del Instituto de Misioneras Seculares y los militantes del apostolado seglar. Finalmente, se examinan los distintos tipos y grados de represión del Estado franquista que sufrieron los sacerdotes obreros y conciliares, debido a su labor de protección y cobertura a la militancia política y sindical durante la clandestinidad, además de su participación como ciudadanos comunes en las protestas antifranquistas y las reivindicaciones de servicios básicos en los barrios obreros de Reus y Tarragona.This doctoral thesis analyses the phenomenon of worker-priests and worker members of religious orders in Reus and Tarragona from 1951 to 1977. It highlights their genesis, path, concerns and aspirations within the framework of Franco’s dictatorship, which was formally allied with the Spanish Catholic Church. In order to reconstruct this historical fact, we examine the contrast between the education they received at the seminaries and ecclesiastical centres where they were trained and the experience they subsequently had in their respective parishes, the working-class neighbourhoods in which they lived, the factories or workshops in which they worked, and the human relationships that arose in the different environments they lived in. The hopes for renewal sparked universally by the Second Vatican Council (1962-1965) within a European context of great ferment and with change in the air in May ‘68, the rise of the youth and student movement, and the Spanish context itself left their mark on a generation of seminarians who began to display social concerns.
In order to contextualise the life experience of the worker-priests and worker members of religious workers in the peripheral neighbourhoods of Reus and Tarragona, we studied the collectives, groups and individuals with whom they shared their vocation to be close to the working class world, where they wove networks of human relationships, solidarity, thought, denunciation and action against Franco’s regime: other priests with different commitments, the female missionaries from the Institute of Secular Missionaries and the militants of the secular apostolate. Finally, we examine the different types and degrees of repression by the Francoist state suffered by worker-priests and council members, due to their work to protect and disguise political and trade union militancy during the underground period, as well as their participation as ordinary citizens in anti-Francoist protests and demands for basic services in the working-class neighbourhoods of Reus and Tarragona
Dinàmica i funcionalitat de KRas en els endosomes
No full textEn els últims anys les endomembranes cel•lulars, especialment les del compariment endocític (endosomes primerencs, EE; tardans LI / MVBs) estan adquirint rellevància com a plataformes de senyalització que poden tenir un paper important en el control de diferents processos cel•lulars com la proliferació o la mobilitat cel•lular. S'ha descrit la presència de diverses GTPasas, entre elles KRas, en els endosomes, les quals són importants per a la senyalització cel•lular. En aquesta tesi s'ha analitzat la dinàmica i la funcionalitat de la GTPasa KRas en els endosomes.
Per poder determinar la quantitat de KRas present en els endosomes i determinar si la seva activació modifica la seva proporció en aquests orgànuls, es va quantificar la presència de GFP-KRas (actiu i inactiu) en els EE. Independentment de l'estat d'activació de KRas, un 10-15% del KRas expressat es troba en els endosomes. Posteriorment, es va analitzar la dinàmica d'associació a la membrana endosomal de KRas. Es conclou que, segons l'estat d'activació que presenti la GTPasa KRas, aquesta s'uneix amb més o menys rapidesa a la membrana dels endosomes, sent més ràpida i més gran la seva recuperació a la membrana quan es troba en la seva forma activa (KRas- GTP).
En aquesta tesi s'analitzen diverses proteïnes d'unió a KRas que podrien potencialment modificar la seva recuperació en la membrana dels endosomes, com la calmodulina (CaM) o la subunitat delta de la fosfodiesterasa 6 (PDEδ). Com a resultat es conclou que la CaM pot modificar la dinàmica de KRas en aquests orgànuls, segurament mitjançant la seva unió a la regió polibàsica quan la serina 181 no es troba fosforilada. Així mateix es demostra que, almenys en les nostres condicions experimentals, la PDEδ no està involucrada en la dinàmica de KRas en els endosomes.
S'ha analitzat el paper de dues fosfolípids principals de la membrana dels endosomes primerencs, el PI3P i el PS (fosfatidilserina), en el reclutament de KRas a la membrana dels endosomes. Els resultats obtinguts demostren una major tendència de KRas per la unió a la PS que als PI3P, però no es descarta que, en absència de PS, KRas pugui unir-se als PI3P.
En l'últim apartat d'aquesta tesi s'estudien diferents funcions de KRas en els endosomes com la seva influència en la mobilitat d'aquests orgànuls oa la mobilitat cel • lular. Es conclou que KRas és important per a la mobilitat dels endosomes i per a la mobilitat cel • lular. També s'analitza el paper de KRas en la localització de la metal•loproteasa MT1-MMP. Mitjançant tècniques bioquímiques i de microscòpia, es demostra que KRas és important, i necessari, perquè la metal•loproteasa es localitzi a la membrana plasmàtica i pugui així exercir la seva missió proteolítica per la degradació de la matriu extracel•lularIn recent years cellular endomembranes, particularly the endocytic compariment (early endosomes, EE; late LE / MVBs) are gaining importance as signaling platforms that can have an important role in the control of various cellular processes such as proliferation or cell mobility. It has been described the presence of several GTPases, including KRas at the endosomes, which are important for cell signaling. This thesis has analyzed the dynamics and functionality of the GTPase KRas in endosomes.
To determine the amount of KRas present at the endosomes andto determine if its activation State changes its proportion in these organelles, the presence of GFP-KRas (active and inactive) was quantified in the EE. Regardless of the state of KRas, 10-15% of KRas expressed in endosomes. Subsequently, the dynamics of endosomal membrane association was analyzed KRas. We conclude that, according to the activation state this GTPase KRas, it recovers more or less rapidly at the membrane of endosomes, being faster and higher its recovery in the membrane when it is in its active form (KRas- GTP).
It has been proposed several binding proteins are discussed KRas recovery could potentially modify KRas recovery at the membrane of endosomes, as calmodulin (CaM) or phosphodiesterase delta 6 (PDEδ) subunit. As a result we conclude that CaM can change the dynamic of KRas at these organelles, probably by binding to the polybasic region when serine 181 is not phosphorylated. It is also shown that, at least in our experimental conditions, the PDEδ is not involved in the dynamics of KRas in endosomes.
We analyzed the role of two major membrane phospholipid of the early endosomes, the PI3P and PS (phosphatidylserine), in the recruitment of KRas on its membrane. The results show a greater tendency of KRas for binding to PS rather than the PI3P, but it is possible that in the absence of PS, KRas could bind to PI3P.
The final section of this thesis KRas different functions are studied in endosomes as their influence on the mobility of these organelles or cell motility. We conclude that KRas is important for the mobility of endosomes and for cel •lular mobility. The role of KRas in locating metalloprotease MT1-MMP has been also analysed. By biochemical and microscopic techniques, we demonstrate that KRas is important and necessary for the metalloprotease to localize at the plasma membrane where it can exert its proteolytic task for the degradation of extracellular matrix
The antilipolytic effect of insulin and epidermal growth factor in rat adipocytes are mediated by different mechanisms
No full textEpidermal growth factor (EGF) and insulin induced similar effects in isolated rat adipocytes. To determine whether EGF and insulin produced similar effects through the same mechanisms, we focused on lipolysis. Insulin inhibited the lipolysis stimulated by isoproterenol, glucagon (either alone or in combination with adenosine deaminase), adenosine deaminase itself, or forskolin. In contrast, EGF did not inhibit the lipolysis stimulated by forskolin or by hormones when the cells were also incubated with adenosine deaminase. The effect of insulin, but not that of EGF, on isoproterenol-stimulated lipolysis disappeared when adipocytes were incubated with 1 microM wortmannin. These results indicate that EGF and insulin affected lipolysis through different mechanisms. We observed that EGF, but not insulin, increased cytosolic Ca2+. The effect of EGF, but not that of insulin, disappeared when the cells were incubated in a Ca2+-free medium. We suggest that EGF, but not insulin, mediate its antilipolytic effect through a Ca2+-dependent mechanism which, however, do not involve Ca2+-activated protein kinase C isoforms. This is based on the following: 1) phorbol 12-myristate 13-acetate affected lipolysis in an opposite way to that of EGF; and 2) the protein kinase C inhibitor bisindolylmaleimide GF 109203X did not affect the antilipolytic action of EGF. Our results indicate that the antilipolytic effect of EGF resembles more that of vasopressin than that of insulin
Clathrin Assembly Lymphoid Myeloid Leukemia (CALM) Protein: Localization in Endocytic-coated Pits, Interactions with Clathrin, and the Impact of Overexpression on Clathrin-mediated Traffic
No full textThe clathrin assembly lymphoid myeloid leukemia (CALM) gene encodes a putative homologue of the clathrin assembly synaptic protein AP180. Hence the biochemical properties, the subcellular localization, and the role in endocytosis of a CALM protein were studied. In vitro binding and coimmunoprecipitation demonstrated that the clathrin heavy chain is the major binding partner of CALM. The bulk of cellular CALM was associated with the membrane fractions of the cell and localized to clathrin-coated areas of the plasma membrane. In the membrane fraction, CALM was present at near stoichiometric amounts relative to clathrin. To perform structure-function analysis of CALM, we engineered chimeric fusion proteins of CALM and its fragments with the green fluorescent protein (GFP). GFP-CALM was targeted to the plasma membrane-coated pits and also found colocalized with clathrin in the Golgi area. High levels of expression of GFP-CALM or its fragments with clathrin-binding activity inhibited the endocytosis of transferrin and epidermal growth factor receptors and altered the steady-state distribution of the mannose-6-phosphate receptor in the cell. In addition, GFP-CALM overexpression caused the loss of clathrin accumulation in the trans-Golgi network area, whereas the localization of the clathrin adaptor protein complex 1 in the trans-Golgi network remained unaffected. The ability of the GFP-tagged fragments of CALM to affect clathrin-mediated processes correlated with the targeting of the fragments to clathrin-coated areas and their clathrin-binding capacities. Clathrin-CALM interaction seems to be regulated by multiple contact interfaces. The C-terminal part of CALM binds clathrin heavy chain, although the full-length protein exhibited maximal ability for interaction. Altogether, the data suggest that CALM is an important component of coated pit internalization machinery, possibly involved in the regulation of clathrin recruitment to the membrane and/or the formation of the coated pit
Differential regulation of RasGAPs in cancer
No full textEver since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell- and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling
Clathrin Assembly Lymphoid Myeloid Leukemia (CALM) Protein: Localization in Endocytic-coated Pits, Interactions with Clathrin, and the Impact of Overexpression on Clathrin-mediated Traffic
No full textThe clathrin assembly lymphoid myeloid leukemia (CALM) gene encodes a putative homologue of the clathrin assembly synaptic protein AP180. Hence the biochemical properties, the subcellular localization, and the role in endocytosis of a CALM protein were studied. In vitro binding and coimmunoprecipitation demonstrated that the clathrin heavy chain is the major binding partner of CALM. The bulk of cellular CALM was associated with the membrane fractions of the cell and localized to clathrin-coated areas of the plasma membrane. In the membrane fraction, CALM was present at near stoichiometric amounts relative to clathrin. To perform structure-function analysis of CALM, we engineered chimeric fusion proteins of CALM and its fragments with the green fluorescent protein (GFP). GFP-CALM was targeted to the plasma membrane-coated pits and also found colocalized with clathrin in the Golgi area. High levels of expression of GFP-CALM or its fragments with clathrin-binding activity inhibited the endocytosis of transferrin and epidermal growth factor receptors and altered the steady-state distribution of the mannose-6-phosphate receptor in the cell. In addition, GFP-CALM overexpression caused the loss of clathrin accumulation in the trans-Golgi network area, whereas the localization of the clathrin adaptor protein complex 1 in the trans-Golgi network remained unaffected. The ability of the GFP-tagged fragments of CALM to affect clathrin-mediated processes correlated with the targeting of the fragments to clathrin-coated areas and their clathrin-binding capacities. Clathrin-CALM interaction seems to be regulated by multiple contact interfaces. The C-terminal part of CALM binds clathrin heavy chain, although the full-length protein exhibited maximal ability for interaction. Altogether, the data suggest that CALM is an important component of coated pit internalization machinery, possibly involved in the regulation of clathrin recruitment to the membrane and/or the formation of the coated pit
Differential regulation of RasGAPs in cancer
No full textEver since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell- and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling
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