title: Altered trafficking of mutated growth factor receptors and their associated molecules: implication for human cancers.
abstract: Ligand-stimulated receptor tyrosine kinases (RTKs) are phosphorylated/ubiquitinated, endocytosed and transported to the lysosomes via endosomes/multivesicular bodies, resulting in the attenuation of signal transmission. If this physiological mechanism of RTK signal downregulation is perturbed, signal transduction persists and may contribute to cellular transformation. This article presents several such examples. In some cases, endocytosis is impaired, and the activated RTK remains on the plasma membrane. In other cases, the activated RTK is endocytosed into endosomes/multivesicular bodies, but not subsequently sorted to the lysosomes for degradation. The latter cases indicate that even endocytosed RTKs can transmit signals. Transport of RTKs is accomplished via the formation and movement of membrane vesicles. Blockage or delay of endocytosis/trafficking can be caused by genetic alterations in the RTK itself or by mutations in CBL, Arf GAPs, or other components involved in internalization and vesicle transport. A survey of the literature indicates that, in some cases, even RTKs synthesized de novo can initiate signaling at the endoplasmic reticulum/Golgi before reaching the plasma membrane. The spectrum of molecules targeted by the signal is likely to be different between cell surface- and endoplasmic reticulum/Golgi-localized RTKs.
authors.affiliation: Institute of Development, Aging and Cancer, Tohoku University; Sendai, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kon
authors.affiliation: Institute of Development, Aging and Cancer, Tohoku University; Sendai, Japan.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Institute of Development, Aging and Cancer, Tohoku University; Sendai, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
keywords: endocytosis; endosomes; lysosomes; membrane vesicles; oncogenesis; receptor tyrosine kinase; signal transduction; ubiquitination