Related Experiment Video

Updated: Jun 5, 2026

Conditional Knockdown of Gene Expression in Cancer Cell Lines to Study the Recruitment of Monocytes/Macrophages to the Tumor Microenvironment
10:59

Conditional Knockdown of Gene Expression in Cancer Cell Lines to Study the Recruitment of Monocytes/Macrophages to the Tumor Microenvironment

Published on: November 23, 2017

c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1

R D Meyer1, D Husain, N Rahimi

  • 1Department of Pathology, Boston University Medical Campus, Boston, MA 02118, USA.

Oncogene
|January 19, 2011
PubMed

Insights

Genetic inactivation of c-Cbl protein enhances tumor angiogenesis and neovascularization by increasing PLCγ1 activation. c-Cbl acts as an angiogenic suppressor by modulating PLCγ1 activity through ubiquitination.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Angiogenesis, the formation of new blood vessels, is crucial for development and disease, regulated by pro- and anti-angiogenic factors.
  • Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) signaling, particularly PLCγ1 activation, plays a key role in angiogenesis.
  • Previous studies identified c-Cbl as a negative regulator of PLCγ1 in endothelial cells, but its in vivo role in angiogenesis was unclear.

Purpose of the Study:

  • To investigate the in vivo role and molecular mechanisms of c-Cbl in regulating angiogenesis.
  • To determine the effect of c-Cbl genetic inactivation on tumor angiogenesis and neovascularization.
  • To elucidate how c-Cbl modulates PLCγ1 activity in response to VEGF stimulation.

Main Methods:

  • Utilized genetically modified mice lacking the c-Cbl gene (c-Cbl null mice).
  • Assessed tumor angiogenesis and retinal neovascularization in c-Cbl null and wild-type mice.
  • Examined endothelial cell proliferation, tube formation, PLCγ1 activation, and intracellular calcium levels.
  • Investigated the mechanism of c-Cbl action, including ubiquitination and tyrosine phosphorylation of PLCγ1.

Main Results:

  • Genetic inactivation of c-Cbl led to enhanced tumor angiogenesis and retinal neovascularization.
  • Endothelial cells from c-Cbl null mice showed increased proliferation and tube formation upon VEGF stimulation.
  • Loss of c-Cbl resulted in robust PLCγ1 activation, increased intracellular calcium, and elevated tyrosine phosphorylation of PLCγ1.
  • c-Cbl-dependent ubiquitination selectively inhibited PLCγ1 tyrosine phosphorylation without causing degradation.

Conclusions:

  • c-Cbl functions as an angiogenic suppressor protein.
  • c-Cbl uniquely modulates PLCγ1 activation via ubiquitination, inhibiting VEGF-driven angiogenesis.
  • These findings reveal a novel molecular mechanism for c-Cbl in controlling blood vessel formation.

Related Concept Videos

Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...