Related Experiment Video

Updated: Oct 20, 2026

Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
10:21

Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells

Published on: February 21, 2018

Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical

S Miyake1, K P Mullane-Robinson, N L Lill

  • 1Lymphocyte Biology Section, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|May 29, 1999
PubMed

Insights

The Cbl proto-oncogene negatively regulates platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta). This regulation requires Cbl's tyrosine kinase binding domain, impacting cell proliferation and survival.

Area of Science:

  • Cellular signaling
  • Oncogene research
  • Receptor tyrosine kinases

Background:

  • The Cbl proto-oncogene is recognized as a negative regulator of tyrosine kinases.
  • Previous studies suggested Cbl negatively regulates PDGFRalpha signaling.
  • Cbl overexpression enhances PDGFRalpha ubiquitination and degradation.

Purpose of the Study:

  • To investigate the role of Cbl in regulating PDGFRbeta signaling.
  • To determine if Cbl negatively regulates PDGFRbeta similarly to PDGFRalpha.
  • To elucidate the mechanism and functional consequences of Cbl-mediated PDGFR regulation.

Main Methods:

  • NIH3T3 cell culture and stimulation with platelet-derived growth factor (PDGF).
  • Analysis of Cbl phosphorylation and association with PDGFRalpha and PDGFRbeta.
  • Assessment of receptor ubiquitination, degradation, and downstream signaling.
  • Mutation of Cbl's tyrosine kinase binding domain (G306E) to assess functional impact.

Main Results:

  • Selective stimulation of PDGFRbeta induced Cbl phosphorylation and association with the receptor.
  • Overexpression of wild-type Cbl enhanced ligand-dependent ubiquitination and degradation of PDGFRbeta.
  • Cbl negatively regulated PDGFRalpha and beta, reducing PDGF-induced cell proliferation and apoptosis.
  • A G306E mutation in Cbl's tyrosine kinase binding domain abrogated its ability to enhance PDGFR ubiquitination/degradation and inhibit cell proliferation/apoptosis.

Conclusions:

  • Cbl negatively regulates PDGFRalpha and PDGFRbeta signaling pathways.
  • This negative regulation is crucial for controlling PDGF-dependent cell proliferation and apoptosis.
  • The tyrosine kinase binding domain of Cbl is essential for its function in PDGFR regulation.

More Related Videos

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence10:09

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

Related Concept Videos

Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
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...
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...
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...