Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis

Abstract

Src family kinases (SFKs) are signaling enzymes that have long been recognized to regulate critical cellular processes such as proliferation, survival, migration, and metastasis. Recently, considerable work has elucidated mechanisms by which SFKs regulate normal and pathologic processes in vascular biology, including endothelial cell proliferation and permeability. Further, when inappropriately activated, SFKs promote pathologic inflammatory processes and tumor metastasis, in part through their effects on the regulation of endothelial monolayer permeability. In this review, we discuss the roles of aberrantly activated SFKs in mediating endothelial permeability in the context of inflammatory states and tumor cell metastasis. We further summarize recent efforts to translate Src-specific inhibitors into therapy for systemic inflammatory conditions and numerous solid organ cancers.

Fig. 1

Mechanism of paracellular transport in endothelial cells. Boxed A Activated Src binds to SH-2 and/or SH-3 regions of myosin light chain kinase (MLCK), leading to its phosphorylation and activation. Myosin-actin crossbridge formation ensues followed by cytoskeletal contraction. Boxed B VE-cadherin and β-catenin in resting complex formation. Upon binding of vascular endothelial growth factor (VEGF) ligand (boxed C), VEGFR undergoes trans-phosphorylation and binds Src at a SH-2 site, resulting in Src phosphorylation and activation. Src then phosphorylates VE-cadherin, resulting in complex dissociation and increased vascular permeability. Boxed D Engagement of integrins with extracellular matrix components results in auto-phosphorylation of focal adhesion kinase (FAK) and an SH-2-binding site to which Src binds. FAK then undergoes Src-dependent phosphorylation and activation at multiple sites, initiating downstream events related to actin assembly and focal adhesion turnover

Fig. 2

Mechanism of transcellular transport in endothelial cells. Albumin, the prototypical macromolecule involved in transcellular transport, binds its receptor, gp60. The gp60 receptors bound to albumin form clusters and interact with calveolin-1. Src then binds the calveolin-1 scaffolding domain and phosphorylates calveolin-1 and gp60. Additional caveolin is activated, as is dynamin-2, initiating vesicle fission and transcellular transport of albumin. Vesicle contents are released on the basolateral surface of the endothelial cell where they affect colloid osmotic pressure