Related Experiment Video

Updated: Sep 21, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation

Hicham Lahlou1, Nathalie Saint-Laurent, Jean-Pierre Estève

  • 1INSERM U531, IFR31, Centre Hospitalier Universitaire Rangueil, 1 avenue Jean Poulhès, 31403 Toulouse Cedex and CNRS Unité Mixte de Recherche 146, Institut Curie, Centre Universitaire, 91405 Orsay Cedex, France.

The Journal of Biological Chemistry
|July 25, 2003
PubMed

Insights

The somatostatin receptor sst2 inhibits cell proliferation by activating the ERK signaling pathway. This novel mechanism involves G protein-coupled receptors, phosphatases, and kinases, ultimately leading to cell cycle regulation.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Endocrinology

Background:

  • The G protein-coupled sst2 somatostatin receptor negatively regulates cell proliferation.
  • sst2 activation leads to tyrosine phosphatase SHP-1 induction, upregulating the cyclin-dependent kinase inhibitor p27Kip1.
  • The precise signaling molecules linking sst2 to p27Kip1 remain to be fully elucidated.

Purpose of the Study:

  • To investigate the signaling pathway connecting the sst2 receptor to p27Kip1 induction.
  • To identify the specific molecular components involved in sst2-mediated regulation of cell proliferation.

Main Methods:

  • Utilized Chinese hamster ovary-DG-44 cells stably expressing sst2 (CHO/sst2) and pancreatic acini from wild-type and sst2 knock-out mice.
  • Employed somatostatin analogue RC-160, MEK1/2 inhibitor PD98059, and dominant-negative mutants.
  • Assessed ERK2 activity, p27Kip1 up-regulation, and insulin-dependent cell proliferation.

Main Results:

  • RC-160 stimulated ERK2 activity in CHO/sst2 cells and wild-type pancreatic acini, but not in sst2 knock-out acini.
  • RC-160-induced p27Kip1 up-regulation and proliferation inhibition were blocked by PD98059.
  • sst2-mediated ERK2 stimulation depended on Gi/o protein, Src, Ras, Rap1, and B-Raf, but not Raf-1.
  • SHP-1, SHP-2, and PI3K were required upstream of Ras and Rap1.

Conclusions:

  • Identified a novel signaling cascade where Gi/o protein-coupled receptor sst2 inhibits cell proliferation.
  • The pathway involves stimulation of ERK signaling through SHP-1, SHP-2, PI3K, Ras, Rap1, B-Raf, and MEK.
  • This provides a new understanding of receptor-mediated control of cell growth.

More Related Videos

Induction and Analysis of Epithelial to Mesenchymal Transition10:37

Induction and Analysis of Epithelial to Mesenchymal Transition

Published on: August 27, 2013

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...