Related Experiment Video

Updated: Aug 22, 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

RNF6 activates the AKT/mTOR signaling pathway by inhibiting PTEN via K27-linked polyubiquitination in myeloma

Yue-Ya Zhong1,2, Li-Huan Zhang1, Zi-Yang Liu3

  • 1Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.

Acta Pharmacologica Sinica
|August 20, 2026
PubMed

Insights

Ring finger protein RNF6 activates AKT/mTOR signaling in multiple myeloma by targeting PTEN for degradation. USP39 counteracts this, while oleandrin inhibits RNF6, offering potential therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Multiple myeloma (MM) is the second most common hematological malignancy.
  • Dysregulated AKT/mTOR signaling is implicated in MM pathogenesis.
  • The precise mechanisms driving AKT/mTOR activation in MM are not fully understood.

Purpose of the Study:

  • To elucidate the role of ring finger protein 6 (RNF6) in activating the AKT/mTOR pathway in multiple myeloma.
  • To investigate the interaction between RNF6, PTEN, and the AKT/mTOR pathway.
  • To identify potential therapeutic targets within this signaling axis.

Main Methods:

  • Investigated RNF6's function as a ubiquitin ligase targeting PTEN.
  • Analyzed PTEN polyubiquitination (specifically K27-linked) and its effect on stability and localization.
  • Assessed the impact of RNF6 and USP39 on AKT/mTOR signaling and glycolysis.
  • Evaluated the effect of oleandrin on RNF6 stability and downstream signaling.

Main Results:

  • RNF6 activates AKT/mTOR signaling by mediating K27-linked polyubiquitination and destabilization of PTEN.
  • RNF6 inhibits PTEN's phosphatase activity and promotes PI(3,4,5)P3 production.
  • USP39 deubiquitinates PTEN, suppressing RNF6-induced AKT/mTOR activation and glycolysis.
  • Oleandrin induces RNF6 degradation, thereby inhibiting the RNF6/PTEN/AKT/mTOR axis.

Conclusions:

  • RNF6 and USP39 are key regulators of PTEN stability and AKT/mTOR signaling in multiple myeloma.
  • The RNF6/PTEN/AKT/mTOR pathway represents a promising therapeutic target for MM.
  • Targeting this axis, potentially with natural products like oleandrin, could offer novel treatment strategies.
Keywords:
Phosphatase and tesin homology deleted on chromosome tenRing finger protein 6multiple myelomaubiquitin specific protease 39

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...
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...
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...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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.