Related Experiment Video

Updated: Jun 19, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

Chunaram Choudhary1, Jesper V Olsen, Christian Brandts

  • 1Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.

Molecular Cell
|October 27, 2009
PubMed

Insights

Oncogenic Flt3-ITD kinase mutations activate different signaling pathways depending on their location within the cell, impacting cancer progression. This spatial regulation influences kinase activity and downstream targets.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Aberrant activation of oncogenic kinases, such as Flt3-ITD, is a hallmark of human cancers.
  • The precise impact of kinase localization on global signaling networks remains incompletely understood.

Purpose of the Study:

  • To investigate the compartment-dependent signaling effects of the oncogenic Flt3-ITD mutant.
  • To elucidate how intracellular localization of Flt3-ITD influences downstream signaling pathways and target activation.

Main Methods:

  • Utilized cell biology techniques to localize Flt3-ITD to the endoplasmic reticulum (ER) or cell membrane.
  • Employed global phosphoproteomics to quantify phosphorylation sites and identify signaling pathway activation.
  • Investigated differential activation of STAT5, PI3K, MAPK, Akt, and Pim kinases.

Main Results:

  • ER-localized Flt3-ITD aberrantly activates STAT5 and its targets (Pim-1/2) but not PI3K/MAPK.
  • Membrane-localized Flt3-ITD strongly activates PI3K/MAPK pathways with reduced STAT5 phosphorylation.
  • Discovered compartment-dependent phosphorylation patterns of Flt3-ITD itself and identified novel signaling components.

Conclusions:

  • Intracellular localization of oncogenic RTKs dictates distinct signaling outputs.
  • Cancer cells may exploit cellular architecture to initiate aberrant signaling cascades via intracellularly activated RTKs.
  • Spatial regulation of kinase activity offers potential therapeutic strategies in oncology.

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

Related Concept Videos

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...
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...
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...
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...
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...
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...