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(Circulation Research. 2006;98:743.)
© 2006 American Heart Association, Inc.

Reviews

Vesicular Trafficking of Tyrosine Kinase Receptors and Associated Proteins in the Regulation of Signaling and Vascular Function

Sanchita Mukherjee^*, Mathewos Tessema^*, Angela Wandinger-Ness

From the Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM.

Correspondence to Angela Wandinger-Ness, Department of Pathology MSC08-4640, 2325 Camino de Salud CRF 225, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-5301. E-mail wness{at}unm.edu

This Review is part of a thematic series on Microdomains in Cardiovascular Signaling, which includes the following articles:

Caveolae and Caveolins in the Cardiovascular System

Focal Adhesion: Paradigm for a Signaling Nexus

Vesicular Trafficking of Tyrosine Kinase Receptors and Associated Proteins in the Regulation of Signaling and Vascular Function

Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of A-Kinase Anchoring Proteins

Targeting Cyclic Nucleotide Signaling

G Protein–Coupled Receptor Trafficking
David A. Kass Editors

Receptor tyrosine kinases (RTKs) play a pivotal role in the development and function of the cardiovascular system. Ligand-activated RTKs promote numerous downstream signal transduction pathways that lead to vascular permeability, as well as proliferation, migration, and differentiation of vascular endothelia and smooth muscle cells. Ligand binding also promotes internalization of the activated receptors either to downregulate the signaling via degradation of the ligand/receptor complex or to signal from endosomes. However, the outcomes of receptor internalization via clathrin-dependent or caveolar pathways and trafficking mechanisms are incompletely clarified in vascular systems. Activity modulation through endocytosis and vesicular trafficking significantly impacts downstream targets of RTKs such as endothelial nitric oxide synthase (eNOS) and VE-cadherin. RTKs and their associated targets are also transported to the nucleus, where they may directly impact nuclear signaling. Although the nuclear transport pathways are just beginning to be unraveled, it appears that endocytosis and vesicular trafficking are involved. In this review, we discuss the mechanisms by which activated RTKs and the downstream targets eNOS and VE-cadherin may be internalized and transported to various intracellular compartments. How localization and interacting proteins impact protein function and influence signaling is an important theme, as is the potential for modulating signaling through therapeutic targeting of activated receptors and components of the endocytic machinery.

Key Words: membrane transport • KDR/Flk-1 • Flt-1 and VEGF receptors • clathrin and caveolae • Erb and EGF receptors • PDGF receptor • insulin and IGF receptors • FGF receptor

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