title: H-ras distribution and signaling in plasma membrane microdomains are regulated by acylation and deacylation events.
abstract: H-Ras must adhere to the plasma membrane to be functional. This is accomplished by posttranslational modifications, including palmitoylation, a reversible process whereby H-Ras traffics between the plasma membrane and the Golgi complex. At the plasma membrane, H-Ras has been proposed to occupy distinct sublocations, depending on its activation status: lipid rafts/detergent-resistant membrane fractions when bound to GDP, diffusing to disordered membrane/soluble fractions in response to GTP loading. Herein, we demonstrate that H-Ras sublocalization is dictated by its degree of palmitoylation in a cell type-specific manner. Whereas H-Ras localizes to detergent-resistant membrane fractions in cells with low palmitoylation activity, it locates to soluble membrane fractions in lineages where it is highly palmitoylated. Interestingly, in both cases GTP loading results in H-Ras diffusing away from its original sublocalization. Moreover, tilting the equilibrium between palmitoylation and depalmitoylation processes can substantially alter H-Ras segregation and, subsequently, its biochemical and biological functions. Thus, the palmitoylation/depalmitoylation balance not only regulates H-Ras cycling between endomembranes and the plasma membrane but also serves as a key orchestrator of H-Ras lateral diffusion between different types of plasma membrane and thereby of H-Ras signaling.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina Santander, Cantabria, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Agudo-Ibáñez
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina Santander, Cantabria, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Herrero
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina Santander, Cantabria, Spain crespop@unican.es.
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
mesh_terms: D000215:Acylation / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation / Q000502:physiology; D061986:MCF-7 Cells; D021962:Membrane Microdomains / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)