Early Endosomal Antigen 1 (EEA1) Is an Obligate Scaffold for Angiotensin II-induced, PKC-α-dependent Akt Activation in Endosomes

Nazarewicz, Ryszard; Salazar, Gloria; Patrushev, Nikolay; Martin, Alejandra San; Hilenski, Lula; Xiong, Shiqin; Alexander, R. Wayne

doi:10.1074/jbc.m110.141499

Cited by 51 publications

(45 citation statements)

References 57 publications

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“…It was recently reported that siRNA-mediated knockdown of EEA1 modulates the activation of PKCα (42). Given our results showing a role for PKCα in the production of infectious virus (Fig.…”

mentioning

confidence: 73%

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

Sharon-Friling

Shenk

2014

Proc. Natl. Acad. Sci. U.S.A.

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The human cytomegalovirus immediate-early protein pUL37x1 induces the release of Ca 2+ stores from the endoplasmic reticulum into the cytosol. This release causes reorganization of the cellular actin cytoskeleton with concomitant cell rounding. Here we demonstrate that pUL37x1 activates Ca 2+ -dependent protein kinase Cα (PKCα). Both PKCα and Rho-associated protein kinases are required for actin reorganization and cell rounding; however, only PKCα is required for the efficient production of virus progeny, arguing that HCMV depends on the kinase for a second function. PKCα activation is also needed for the production of large (1-5 μm) cytoplasmic vesicles late after infection. The production of these vesicles is blocked by inhibition of fatty acid or phosphatidylinositol-3-phosphate biosynthesis, and the failure to produce vesicles is correlated with substantially reduced production of enveloped virus capsids. These results connect earlier work identifying a requirement for lipid synthesis with specific morphological changes, and support the argument that the PKCα-induced large vesicles are either required for the efficient production of mature virus particles or serve as a marker for the process.capsid envelopment | virion assembly | virus-induced membranes

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confidence: 73%

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

Sharon-Friling

Shenk

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, the stronger expression of several components of the mTOR pathway in the reticularis could suggest a role of this pathway in the androgen production and the stronger expression of these components in the glomerulosa may be related to angiotensin II-induced activation of the mTOR pathway (Nazarewicz et al 2011). We did not perform a real comparison between the staining observed in NAs and that observed in ATs because the presence of different layers in NAs, expressing the evaluated proteins at different intensities, made it difficult to attribute a semiquantitative IHC score as done for tumors.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors

Martino¹,

Feelders²,

Herder³

et al. 2014

Endocrine-Related Cancer

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The mTOR pathway has recently been suggested as a new potential target for therapy in adrenocortical carcinomas (ACCs). The aim of the current study is to describe the expression of the mTOR pathway in normal adrenals (NAs) and pathological adrenals and to explore whether there are correlation between the expression of these proteins and the in vitro response to sirolimus. For this purpose, the MTOR, S6K1 (RPS6KB1), and 4EBP1 (EIF4EBP1) mRNA expression were evaluated in ten NAs, ten adrenal hyperplasias (AHs), 17 adrenocortical adenomas (ACAs), and 17 ACCs by qPCR, whereas total(t)/phospho(p)-MTOR, t/p-S6K, and t/p-4EBP1 protein expression were assessed in three NAs, three AHs, six ACAs, and 20 ACCs by immunohistochemistry. The effects of sirolimus on cell survival and/or cortisol secretion in 12 human primary cultures of adrenocortical tumors (ATs) were also evaluated. In NAs and AHs, layer-specific expression of evaluated proteins was observed. S6K1 mRNA levels were lower in ACCs compared with NAs, AHs, and ACAs (P!0.01). A subset of ATs presented a moderate to high staining of the evaluated proteins. Median t-S6K1 protein expression in ACCs was lower than that in ACAs (P!0.01). Moderate to high staining of p-S6K1 and/or p-4EBP1 was observed in most ATs. A subset of ACCs not having moderate to high staining had a higher Weiss score than others (P!0.029). In primary AT cultures, sirolimus significantly reduced cell survival or cortisol secretion only in sporadic cases. In conclusion, these data suggest the presence of an activated mTOR pathway in a subset of ATs and a possible response to sirolimus only in certain ACC cases.

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“…Endosome-specific signaling of EGFR has also been shown to activate PI3K/Akt signaling (55,56). In addition, the endosomal proteins EEA1 and Appl1 (adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1) serve as scaffolding proteins that promote endosomal Akt recruitment, phosphorylation, and activation (57,58). Garcia-Regalado and colleagues (59) showed that the Lipophosphatidic acid-stimulated interaction between Rab11a and the heterotrimeric G protein subunit Gbg on endosomes contributes to the recruitment and activation of PI3K and Akt on these endosomal compartments.…”

Section: Discussionmentioning

confidence: 99%

The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a

Morrow

Alipour

Bridges

et al. 2014

Molecular Cancer Research

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Early Endosomal Antigen 1 (EEA1) Is an Obligate Scaffold for Angiotensin II-induced, PKC-α-dependent Akt Activation in Endosomes

Cited by 51 publications

References 57 publications

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles

Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors

The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a

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