Related Experiment Video

Updated: Sep 22, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.2K

AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis

Hyunjoo Kim1, Muhah Jeong1, Do-Hyeong Na1

  • 1School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826, Korea.

Cell Death & Disease
|May 18, 2022
PubMed

Insights

Adenylate kinase 2 (AK2) suppresses tumor growth by inhibiting BRAF signaling, linking cellular energy levels to cancer proliferation. AK2 acts as a BRAF-suppressor, negatively regulating this key cancer pathway.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • RAS-BRAF signaling is crucial for cell proliferation and frequently mutated in human cancers.
  • Adenylate kinase 2 (AK2) influences cell death and proliferation, but its role in tumorigenesis requires mechanistic clarification.
  • Previous studies implicated AK2 in certain cancers, yet its precise function in tumor suppression remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which AK2 regulates BRAF signaling in cancer.
  • To investigate the interaction between AK2, BRAF, and cellular metabolic state.
  • To determine AK2's role as a potential tumor suppressor in hepatocellular carcinoma (HCC).

Main Methods:

  • In vitro biochemical assays to assess AK2-BRAF interaction and BRAF activity.
  • Cellular models (knockdown/knockout) to study AK2's effect on proliferation and signaling.
  • Analysis of patient tumor tissues and microarray datasets (TCGA-LIHC, GSE14520) for AK2 expression and ERK activation.
  • In vivo mouse models of HRAS-driven HCC to evaluate AK2's role in tumor growth.

Main Results:

  • AK2 directly binds to BRAF, inhibiting its activity and downstream ERK phosphorylation.
  • AK2-BRAF interaction is enhanced by cellular energy deprivation and AMP binding to AK2, linking metabolic status to pathway regulation.
  • Low AK2 expression correlates with increased BRAF/ERK activity and proliferation in HCC cell lines and patient tumors.
  • RAS activation abrogates AK2-BRAF interaction, while AK2 inhibits BRAF mutants, suggesting a broad suppressive role.

Conclusions:

  • AK2 acts as a metabolic sensor and a negative regulator of BRAF signaling, connecting cellular energy levels to cancer cell proliferation.
  • AK2 functions as a tumor suppressor by inhibiting BRAF activity, particularly in RAS-driven cancers and against BRAF inhibitor resistance.
  • Downregulation of AK2 is a potential driver of tumorigenesis, highlighting AK2 as a therapeutic target.

More Related Videos

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells06:44

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

1.2K
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

287

Related Concept Videos

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...
3.9K
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...
4.1K
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...
6.3K
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...
6.5K
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...
10.1K
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...
4.6K