Phosphatidylinositol 3-Kinase and Rab5 GTPase Inversely Regulate the Smad Anchor for Receptor Activation (SARA) Protein Independently of Transforming Growth Factor-β1

Runyan, Constance E.; Liu, Zongyi; Schnaper, H. William

doi:10.1074/jbc.m112.380493

Cited by 20 publications

(20 citation statements)

References 43 publications

(31 reference statements)

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“…Growing evidences suggest that membrane-bound phosphoinositides regulate Rab-mediated endosome trafficking [ 61 , 62 ], and the metabolism of phosphoinositides was affected by the disruption of insulin signaling [ 63 – 65 ]. Recent studies also showed that Rab activity is affected by insulin signaling and that PI3K inhibition causes upregulation of Rab5 [ 66 , 67 ]. In the present study, we observed amyloid deposition in the pancreatic islets of all adult monkeys with DM.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus Accelerates Aβ Pathology in Brain Accompanied by Enhanced GAβ Generation in Nonhuman Primates

et al. 2015

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Growing evidence suggests that diabetes mellitus (DM) is one of the strongest risk factors for developing Alzheimer’s disease (AD). However, it remains unclear why DM accelerates AD pathology. In cynomolgus monkeys older than 25 years, senile plaques (SPs) are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. In laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 DM. In the present study, we performed histopathological and biochemical analyses of brain tissue in cynomolgus monkeys with type 2 DM to clarify the relationship between DM and AD pathology. Here, we provide the evidence that DM accelerates Aβ pathology in vivo in nonhuman primates who had not undergone any genetic manipulation. In DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices, even in monkeys younger than 20 years. Biochemical analyses of brain revealed that the amount of GM1-ganglioside-bound Aβ (GAβ)—the endogenous seed for Aβ fibril formation in the brain—was clearly elevated in DM-affected monkeys. Furthermore, the level of Rab GTPases was also significantly increased in the brains of adult monkeys with DM, almost to the same levels as in aged monkeys. Intraneuronal accumulation of enlarged endosomes was also observed in DM-affected monkeys, suggesting that exacerbated endocytic disturbance may underlie the acceleration of Aβ pathology due to DM.

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Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus Accelerates Aβ Pathology in Brain Accompanied by Enhanced GAβ Generation in Nonhuman Primates

et al. 2015

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“…Similarly, the loss of function of SARA did not affect TGF-␤-induced Smad activation, Smad nuclear translocation, or the expression of TGF-␤-target gene expression in HeLa cells (69). Third, endogenous regulation of SARA is produced by phosphatidylinositol 3-kinase (PI3K) activity independently of TGF-␤, indicating that the mechanism of PI3K inhibition-mediated SARA downregulation differs from that induced by TGF-␤ in human kidney cells (HCKs) (70). Fourth, the internalization of T␤Rs into EEs is not affected in mouse embryonic fibroblasts (MEFs) derived from SARA mutant mice lacking the FYVE domain (4).…”

Section: Going Out Of Endosomal Trafficking: Differential Roles Of Samentioning

confidence: 99%

New Player in Endosomal Trafficking: Differential Roles of Smad Anchor for Receptor Activation (SARA) Protein

Rozés-Salvador

Siri

Musri

et al. 2018

Molecular and Cellular Biology

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The development and maintenance of multicellular organisms require specialized coordination between external cellular signals and the proteins receiving stimuli and regulating responses. A critical role in the proper functioning of these processes is played by endosomal trafficking, which enables the transport of proteins to targeted sites as well as their return to the plasma membrane through its essential components, the endosomes. During this trafficking, signaling pathways controlling functions related to the endosomal system are activated both directly and indirectly. Although there are a considerable number of molecules participating in these processes, some are more known than others for their specific functions. Toward the end of the 1990s, Smad anchor for receptor activation (SARA) protein was described to be controlling and to facilitate the localization of Smads to transforming growth factor β (TGF-β) receptors during TGF-β signaling activation, and, strikingly, SARA was also identified to be one of the proteins that bind to early endosomes (EEs) participating in membrane trafficking in several cell models. The purpose of this review is to analyze the state of the art of the contribution of SARA in different cell types and cellular contexts, focusing on the biological role of SARA in two main processes, trafficking and cellular signaling, both of which are necessary for intercellular coordination, communication, and development.

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“…Finally, although highly controversial (Bakkebø et al, 2012;Runyan et al, 2012), SARA has been reported to be important for activation of the TGFβ signaling pathway (Tsukazaki et al, 1998;Itoh et al, 2002). Whether this functional aspect of SARA plays a role in L1 surface expression remains to be investigated.…”

Section: Sara Regulates the Surface Expression Of L1mentioning

confidence: 99%

SARA regulates neuronal migration during neocortical development through L1 trafficking

et al. 2016

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Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppressioninduced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.

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Phosphatidylinositol 3-Kinase and Rab5 GTPase Inversely Regulate the Smad Anchor for Receptor Activation (SARA) Protein Independently of Transforming Growth Factor-β1

Cited by 20 publications

References 43 publications

Diabetes Mellitus Accelerates Aβ Pathology in Brain Accompanied by Enhanced GAβ Generation in Nonhuman Primates

Diabetes Mellitus Accelerates Aβ Pathology in Brain Accompanied by Enhanced GAβ Generation in Nonhuman Primates

New Player in Endosomal Trafficking: Differential Roles of Smad Anchor for Receptor Activation (SARA) Protein

SARA regulates neuronal migration during neocortical development through L1 trafficking

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