RESUMEN
BACKGROUND: Striatin, a putative protein phosphatase 2A (PP2A) B-type regulatory subunit, is a multi-domain scaffolding protein that has recently been linked to several diseases including cerebral cavernous malformation (CCM), which causes symptoms ranging from headaches to stroke. Striatin association with the PP2A A/C (structural subunit/catalytic subunit) heterodimer alters PP2A substrate specificity, but targets and roles of striatin-associated PP2A are not known. In addition to binding the PP2A A/C heterodimer to form a PP2A holoenzyme, striatin associates with cerebral cavernous malformation 3 (CCM3) protein, the mammalian Mps one binder (MOB) homolog, Mob3/phocein, the mammalian sterile 20-like (Mst) kinases, Mst3, Mst4 and STK25, and several other proteins to form a large signaling complex. Little is known about the molecular architecture of the striatin complex and the regulation of these sterile 20-like kinases. RESULTS: To help define the molecular organization of striatin complexes and to determine whether Mst3 might be negatively regulated by striatin-associated PP2A, a structure-function analysis of striatin was performed. Two distinct regions of striatin are capable of stably binding directly or indirectly to Mob3--one N-terminal, including the coiled-coil domain, and another more C-terminal, including the WD-repeat domain. In addition, striatin residues 191-344 contain determinants necessary for efficient association of Mst3, Mst4, and CCM3. PP2A associates with the coiled-coil domain of striatin, but unlike Mob3 and Mst3, its binding appears to require striatin oligomerization. Deletion of the caveolin-binding domain on striatin abolishes striatin family oligomerization and PP2A binding. Point mutations in striatin that disrupt PP2A association cause hyperphosphorylation and activation of striatin-associated Mst3. CONCLUSIONS: Striatin orchestrates the regulation of Mst3 by PP2A. It binds Mst3 likely as a dimer with CCM3 via residues lying between striatin's calmodulin-binding and WD-domains and recruits the PP2A A/C heterodimer to its coiled-coil/oligomerization domain. Residues outside the previously reported coiled-coil domain of striatin are necessary for its oligomerization. Striatin-associated PP2A is critical for Mst3 dephosphorylation and inactivation. Upon inhibition of PP2A, Mst3 activation appears to involve autophosphorylation of multiple activation loop phosphorylation sites. Mob3 can associate with striatin sequences C-terminal to the Mst3 binding site but also with sequences proximal to striatin-associated PP2A, consistent with a possible role for Mob 3 in the regulation of Mst3 by PP2A.
Asunto(s)
Proteínas de Unión a Calmodulina/química , Proteínas de Unión a Calmodulina/metabolismo , Sistema Nervioso Central/patología , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Unión a Calmodulina/genética , Sistema Nervioso Central/metabolismo , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Complejos Multiproteicos/genética , Proteínas del Tejido Nervioso/genética , Fosforilación , Unión Proteica , Multimerización de Proteína , Proteína Fosfatasa 2/genética , Proteínas Serina-Treonina Quinasas/genética , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Especificidad por Sustrato , Activación TranscripcionalRESUMEN
OBJECTIVE: Home visiting programs for very young children seek to promote their health and development. We conducted a process and outcome evaluation of the Postpartum/Newborn Home Visit (PPNBHV) service in 1 county. DESIGN: A retrospective study of Aiken County Health records of live infant births in 2004 was conducted. SAMPLE: A random sample of 176 infants who were born in 2004 and enrolled in the women, infants, and children's (WIC) program in the same year was selected. MEASURES: Process measures include timeliness of the home visit, and appropriateness of revisits. Outcome measures include age at WIC enrollment and immunization status at 6/9 months. RESULTS: Of the 176 infants, 76 (43%) received a home visit. Of these, 13 (17%) received the visit within the stipulated time frame. After controlling for potential confounders, infants who received a home visit were 4 times (95% CI 1.92-8.36) as likely to enroll early in the WIC program compared with those who did not. CONCLUSION: The PPNBHV service may contribute to early enrollment in the WIC program. Improvement in the timeliness of the visits is needed. Program monitoring and evaluation are necessary to ensure adherence, measure outcomes, and provide feedback for continuous quality improvement.
