Altered trafficking of mutated growth factor receptors and their associated molecules: implication for human cancers

Area of Science:

• Cell Biology
• Molecular Biology
• Oncology

Background:

• Ligand-stimulated receptor tyrosine kinases (RTKs) are crucial signaling molecules involved in cellular communication.
• Proper downregulation of RTK signaling, through endocytosis and lysosomal degradation, is essential for preventing aberrant cell growth.
• Perturbations in RTK trafficking pathways can disrupt signal attenuation, leading to sustained signaling.

Purpose of the Study:

• To review and present examples of perturbed RTK signal downregulation mechanisms.
• To illustrate how defects in endocytosis and lysosomal transport of RTKs contribute to cellular transformation.
• To explore the consequences of RTK signaling initiated at the endoplasmic reticulum/Golgi.

Main Methods:

• Literature survey and review of existing studies on RTK signaling and trafficking.
• Analysis of genetic alterations in RTKs, CBL, Arf GAPs, and other trafficking components.
• Examination of RTK signaling initiated at intracellular compartments like the endoplasmic reticulum/Golgi.

Main Results:

• Impaired endocytosis can lead to activated RTKs persisting on the plasma membrane, prolonging signaling.
• Defective lysosomal sorting of endocytosed RTKs allows for continued signal transmission from endosomes/multivesicular bodies.
• RTKs can initiate signaling at the endoplasmic reticulum/Golgi before reaching the plasma membrane, with potentially different downstream targets.

Conclusions:

• Perturbations in the physiological downregulation of RTK signaling are implicated in cellular transformation and disease.
• Both impaired internalization and defective intracellular trafficking of RTKs can lead to persistent oncogenic signaling.
• The cellular localization of RTK signaling (cell surface vs. intracellular compartments) influences the spectrum of targeted molecules.