The SHP-1 tyrosine phosphatase is a negative regulator of ghrelin activity, being a critical signaling component for proper regulation of Akt-dependent processes. Based on the SHP-1 expression pattern in white adipose tissue (WAT) and its regulation in a positive energy balance situation, it is possible to speculate about its role in the enlargement of WAT in obesity

Alvarez SE

Begoña O. Alén

Camiña JP

Carlos S. Mosteiro

Castañeda TR

Cuevas B

Cuevas BD

Daniel Beiroa

Després JP

Dubois MJ

Felipe F. Casanueva

Feng YH

Frank C

Gurriarán-Rodríguez U

Holliday ND

Imani F

Jesus P. Camiña

Jonathan Chernoff

Klingmüller U

Kovacs JJ

Kozlowski M

Krautwald S

Lodeiro M

Lorenz U

Manning BD

Maria Lodeiro

Marily Theodoropoulou

María Pardo

Neel BG

Norris K

Pagès P

Plutzky J

Rosalía Gallego

Rubén Nogueiras

Somani AK

Theodoropoulou M

Tonks NK

Uchida T

Wajchenberg BL

Wells T

Wishcamper CA

Xu J

Yolanda Pazos

Yu Z

Zhang HH

Zhang J

Zhang Z

PubMed

Lodeiro, M.

Alen, B.

Mosteiro, C.

Beiroa, D.

Nogueiras, R.

Theodoropoulou, M.

Pardo, M.

Gallego, R.

Pazos, Y.

Casanueva, F.

Camina, J.

MPG.PuRe

The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system

The aim of the present study was to identify the signaling mechanism(s) responsible for the modulation of growth hormone secretagogue receptor type 1a (GHSR1a)-associated Akt activity. Ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early Gi/oprotein-dependent pathway and a late pathway mediated by β-arrestins. We found that the Src homology 2–containing protein tyrosine phosphatase (SHP-1) was an essential molecule in both Gi/oprotein–dependent and β-arrestin–mediated pathways. More specifically, the role of SHP-1 in the Gi/oprotein–dependent pathway was demonstrated by the fact that the overexpression of a catalytically defective SHP-1 augments tyrosine phosphorylation of the PI3K regulatory subunit p85, leading to an increase in the phosphorylation of cSrc and phosphoinositide-dependent protein kinase 1, and finally activating Akt. The presence of SHP-1 in the β-arrestin–scaffolded complex and its attenuating effect on the cSrc and Akt activities verified that SHP-1 regulates not only the Gi/oprotein–dependent pathway but also the β-arrestin–mediated pathway. Assays performed in preadipocyte and adipocyte 3T3-L1 cells showed SHP-1 expression. According to our results in HEK-GHSR1a cells, ghrelin stimulated SHP-1 phosphorylation in 3T3-L1 cells. The increase in ghrelin-induced Akt activity was enhanced by small interfering RNA of SHP-1 in preadipocyte 3T3-L1 cells. These results were reproduced in white adipose tissue obtained from mice, in which SHP-1 exhibited higher expression in omental than in subcutaneous tissue. Furthermore, this pattern of expression was inverted in mice fed a high-fat diet, suggesting a role for SHP-1 in controlling ghrelin sensitivity in adipose tissue. Indeed, SHP-1 deficiency was associated with augmented ghrelin-evoked Akt phosphorylation in omental tissue, as well as decreased phosphorylation under overexpression of SHP-1 in subcutaneous tissue. These findings showed a novel role for SHP-1 in the regulation of Akt activity through the modulation of the ghrelin/GHSR1a system signaling.</jats:p

Crossref

Molecular Biology of the Cell

The aim of the present study was to identify the signaling mechanism(s) responsible for the modulation of growth hormone secretagogue receptor type 1a (GHSR1a)-associated Akt activity. Ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early G(i/o) protein-dependent pathway and a late pathway mediated by beta-arrestins. We found that the Src homology 2-containing protein tyrosine phosphatase (SHP-1) was an essential molecule in both G(i/o) protein-dependent and beta-arrestin-mediated pathways. More specifically, the role of SHP-1 in the G(i/o) protein-dependent pathway was demonstrated by the fact that the overexpression of a catalytically defective SHP-1 augments tyrosine phosphorylation of the PI3K regulatory subunit p85, leading to an increase in the phosphorylation of cSrc and phosphoinositide-dependent protein kinase 1, and finally activating Akt. The presence of SHP-1 in the beta-arrestin-scaffolded complex and its attenuating effect on the cSrc and Akt activities verified that SHP-1 regulates not only the G(i/o) protein-dependent pathway but also the beta-arrestin-mediated pathway. Assays performed in preadipocyte and adipocyte 3T3-L1 cells showed SHP-1 expression. According to our results in HEK-GHSR1a cells, ghrelin stimulated SHP-1 phosphorylation in 3T3-L1 cells. The increase in ghrelin-induced Akt activity was enhanced by small interfering RNA of SHP-1 in preadipocyte 3T3-L1 cells. These results were reproduced in white adipose tissue obtained from mice, in which SHP-1 exhibited higher expression in omental than in subcutaneous tissue. Furthermore, this pattern of expression was inverted in mice fed a high-fat diet, suggesting a role for SHP-1 in controlling ghrelin sensitivity in adipose tissue. Indeed, SHP-1 deficiency was associated with augmented ghrelin-evoked Akt phosphorylation in omental tissue, as well as decreased phosphorylation under overexpression of SHP-1 in subcutaneous tissue. These findings showed a novel role for SHP-1 in the regulation of Akt activity through the modulation of the ghrelin/GHSR1a system signaling

Lodeiro Pose, María

OTERO OTERO, BEGOÑA

SEOANE SUAREZ, CARLOS

Beiroa Tarrío, Daniel

Nogueiras Pozo, Rubén

Theodoropoulou,  Marily

Pardo Pérez, María

Gallego, Rosalía

Pazos Randulfe, Yolanda

Casanueva Freijo, Felipe

Pérez Camiña, Jesús

RUNA -  Repositorio de Saúde

English

https://runa.sergas.gal/xmlui/bitstream/20.500.11940/5551/1/Lodeiro%20et%20al.%20-%202011%20-%20The%20SHP-1%20protein%20tyrosine%20phosphatase%20negatively%20.pdf

The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system

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RUNA - Repositorio de Saúde