RGD Reference Report - A novel player in cellular hypertrophy: Gibetagamma/PI3K-dependent activation of the RacGEF TIAM-1 is required for alpha(1)-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes. - Rat Genome Database

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A novel player in cellular hypertrophy: Gibetagamma/PI3K-dependent activation of the RacGEF TIAM-1 is required for alpha(1)-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes.

Authors: Vettel, C  Wittig, K  Vogt, A  Wuertz, CM  El-Armouche, A  Lutz, S  Wieland, T 
Citation: Vettel C, etal., J Mol Cell Cardiol. 2012 Aug;53(2):165-75. doi: 10.1016/j.yjmcc.2012.04.015. Epub 2012 May 4.
RGD ID: 9835036
Pubmed: PMID:22564263   (View Abstract at PubMed)
DOI: DOI:10.1016/j.yjmcc.2012.04.015   (Journal Full-text)

Activation of alpha(1)-adrenoceptors (alpha(1)-AR) by high catecholamine levels, e.g. in heart failure, is thought to be a driving force of cardiac hypertrophy. In this context several downstream mediators and cascades have been identified to potentially play a role in cardiomyocyte hypertrophy. One of these proteins is the monomeric G protein Rac1. However, until now it is unclear how this essential G protein is activated by alpha(1)-AR agonists and what are the downstream targets inducing cellular growth. By using protein-based as well as pharmacological inhibitors and the shRNA technique, we demonstrate that in neonatal rat cardiomyocytes (NRCM) Rac1 is activated via a cascade involving the alpha(1A)-AR subtype, G(i)betagamma, the phosphoinositide-3'-kinase and the guanine nucleotide exchange factor Tiam1. We further demonstrate that this signaling induces an increase in protein synthesis, cell size and atrial natriuretic peptide expression. We identified the p21-activated kinase 2 (PAK2) as a downstream effector of Rac1 and were able to link this cascade to the activation of the pro-hypertrophic kinases ERK1/2 and p90RSK. Our data thus reveal a prominent role of the alpha(1A)-AR/G(i)betagamma/Tiam1-mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cardiac muscle hypertrophy  IEP 9835036 RGD 
cardiac muscle hypertrophy  IMP 9835036 RGD 
regulation of ERK1 and ERK2 cascade  IMP 9835036 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pak2  (p21 (RAC1) activated kinase 2)
Tiam1  (TIAM Rac1 associated GEF 1)


Additional Information