Faculty Collaboration Database

Biphasic activation of p21ras by endothelin-1 sequentially activates the ERK cascade and phosphatidylinositol 3-kinase. EMBO J 1997 Nov 03;16(21):6439-51

Date

11/14/1997

Pubmed ID

9351826

Pubmed Central ID

PMC1170250

DOI

10.1093/emboj/16.21.6439

Scopus ID

2-s2.0-0031551588 (requires institutional sign-in at Scopus site)   143 Citations

Abstract

Endothelin-1 (ET-1) induces cell proliferation and differentiation through multiple G-protein-linked signaling systems, including p21ras activation. Whereas p21ras activation and desensitization by receptor tyrosine kinases have been extensively investigated, the kinetics of p21ras activation induced by engagement of G-protein-coupled receptors remains to be fully elucidated. In the present study we show that ET-1 induces a biphasic activation of p21ras in rat glomerular mesangial cells. The first peak of activation of p21ras, at 2-5 min, is mediated by immediate association of phosphorylated Shc with the guanosine exchange factor Sos1 via the adaptor protein Grb2. This initial activation of p21ras results in activation of the extracellular signal-regulated kinase (ERK) cascade. We demonstrate that ET-1 signaling elicits a negative feedback mechanism, modulating p21ras activity through ERK-dependent Sos1 phosphorylation, findings which were confirmed using an adenovirus MEK construct. Subsequent to p21ras and ERK deactivation, Sos1 reverts to the non-phosphorylated condition, enabling it to bind again to the Grb2/Shc complex, which is stabilized by persistent Shc phosphorylation. However, the resulting secondary activation of p21ras at 30 min does not lead to ERK activation, correlating with intensive, ET-1-induced expression of MAP kinase phosphatase-1, but does result in increased p21ras-associated phosphatidylinositol 3-kinase activity. Our data provide evidence that ET-1-induced biphasic p21ras activation causes sequential stimulation of divergent downstream signaling pathways.

Author List

Foschi M, Chari S, Dunn MJ, Sorokin A

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Animals
Cell Cycle Proteins
Cells, Cultured
Dual Specificity Phosphatase 1
Endothelin-1
Enzyme Activation
GRB2 Adaptor Protein
Glomerular Mesangium
Guanine Nucleotide Exchange Factors
Immediate-Early Proteins
Kinetics
Male
Models, Biological
Phosphatidylinositol 3-Kinases
Phosphoprotein Phosphatases
Phosphorylation
Protein Phosphatase 1
Protein Processing, Post-Translational
Protein Tyrosine Phosphatases
Proteins
Proto-Oncogene Proteins p21(ras)
Rats
Rats, Sprague-Dawley
Receptors, Endothelin
Recombinant Fusion Proteins
Shc Signaling Adaptor Proteins
Signal Transduction
Src Homology 2 Domain-Containing, Transforming Protein 1
ras Guanine Nucleotide Exchange Factors