AKT is highly phosphorylated in pheochromocytomas but not in benign adrenocortical tumors

Martin Fassnacht1, Dirk Weismann, Silke Ebert

  • 1Department of Medicine, Endocrine and Diabetes Unit, University of Würzburg, 97080 Würzburg, Germany. Fassnacht_m@medizin.uni-wuerzburg.de

Abstract

Insights

Increased AKT activation is implicated in pheochromocytomas, a finding not observed in adrenocortical adenomas. This study investigated AKT

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Activation of AKT is a significant factor in numerous human cancers.
  • Pten gene heterozygous deletion in mice correlates with increased AKT activation and pheochromocytoma development.
  • Understanding AKT's role is crucial for diagnosing and treating adrenal tumors.

Purpose of the Study:

  • To investigate the role of AKT in the pathogenesis of pheochromocytomas.
  • To examine AKT's role in the development of adrenocortical tumors.

Main Methods:

  • Western blot analysis was used to quantify total AKT and phosphorylated AKT (pAKT) levels.
  • Immunohistochemistry was performed to assess AKT and pAKT expression in tumor tissues.
  • PTEN protein expression and loss of heterozygosity were analyzed in pheochromocytomas.

Main Results:

  • Total AKT expression was elevated in pheochromocytomas and adrenocortical carcinomas (ACC) compared to normal adrenals.
  • The pAKT/AKT ratio was significantly increased in pheochromocytomas but not in ACC or other adenomas.
  • No PTEN loss of heterozygosity or decreased PTEN protein was found in pheochromocytomas.

Conclusions:

  • Evidence suggests increased AKT activation in pheochromocytomas.
  • AKT activation is not significantly increased in common adrenocortical adenomas.
  • These findings differentiate the molecular pathways in pheochromocytomas versus adrenocortical adenomas.

Related Concept Videos

cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Phosphorylation01:02

Phosphorylation

The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Adrenergic Receptors: β Subtype01:26

Adrenergic Receptors: β Subtype

β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors have equal affinities for...