NHERF1 recruits the tumor suppressors PTEN and PHLPP to synergistically inhibit the PI-3K pathway

Glioblastoma multiforme is the most common form of brain cancer that presents patients with a poor prognosis that has remained unchanged over the past few decades. The tumor suppressor phosphatase PTEN antagonizes one of the major oncogenic pathways involved in the progression of glioblastoma, and is frequently deleted in this cancer type. Contrary to our expectations, we found that most glioblastoma cells expressing endogenous PTEN also harbor basal PI-3K/AKT activation mainly attributable to impaired PTEN membrane localization. This alteration correlated with a shift of the adaptor protein NHERF1, which contributes to PTEN membrane recruitment in normal cells, from the membrane to the cytoplasm. In cells expressing membrane-localized NHERF1, only simultaneous PTEN and NHERF1 depletion achieved AKT activation, suggesting the involvement of additional PI-3K/AKT suppressor regulated by NHERF1. We identified these novel interactors of NHERF1 as the PHLPP1 and PHLPP2 phosphatases. ^ NHERF1 directly interacted and recruited both PHLPP proteins to the membrane and, through both NHERF1 PDZ domains, assembled ternary complexes consisting of PTEN-NHERF1-PHLPP. Only simultaneous depletion of PTEN and PHLPP1 significantly activated AKT and increased proliferation in cells with membrane-localized NHERF1. Analysis of glioblastoma human tumors revealed frequent loss of membrane-localized NHERF1. On the other hand, targeting of NHERF1 to the membrane achieved suppression of AKT and cell proliferation. Our findings reveal a novel mechanism for PI-3K/AKT regulation by the synergistic cooperation between two important tumor suppressors, PTEN and PHLPP, via the scaffold protein NHERF1. ^

Seder Eliyahu rabah ṿe-seder Eliyahu zuṭa : ha-muvaʾim be-shem Tana de-ve Eliyahu : ʿa.pi k.y. Romi mi-shenat 833 : ʿim hosafat Meʾir ʿayin u-mavo ...

hotsetim la-or ani Meʾir Ish Shalom

Primera revision del proyecto de ordenacion del monte "Montaña de Pi". Numero 45 del catalogo de los de utilidad publica de la provincia de Lerida, perteneciente al pueblo de Pi (Bellver)

El presente trabajo de Revisión del Proyecto de Ordenación del monte "Montaña de Pi" (Bellver), perteneciente al citado pueblo, nos fue encomendado por la Dirección General de Montes, Caza y Pesca fluvial, por orden de fecha 11de Agosto de 1943

Comparing fuzzy and intelligent PI controllers in stop-and-go manoeuvres

The aim of this work was twofold: on the one hand, to describe a comparative study of two intelligent control techniques-fuzzy and intelligent proportional-integral (PI) control, and on the other, to try to provide an answer to an as yet unsolved topic in the automotive sector-stop-and-go control in urban environments at very low speeds. Commercial vehicles exhibit nonlinear behavior and therefore constitute an excellent platform on which to check the controllers. This paper describes the design, tuning, and evaluation of the controllers performing actions on the longitudinal control of a car-the throttle and brake pedals-to accomplish stop-and-go manoeuvres. They are tested in two steps. First, a simulation model is used to design and tune the controllers, and second, these controllers are implemented in the commercial vehicle-which has automatic driving capabilities-to check their behavior. A stop-and-go manoeuvre is implemented with the two control techniques using two cooperating vehicles.