In addition to soluble factors, the extracellular matrix (ECM) also plays a vital role in normal vasculogenesis and in the pathological angiogenesis of many disease states. Here we will review what is known about the role of the ECM molecules fibronectin and tenascin-C in the vasculature and highlight a potential collaborative interplay between these molecules in developmental and tumorigenic angiogenesis. We will address the evolution of these modular proteins, their cellular interactions and how they become assembled into an insoluble matrix that impacts the assembly of other ECM proteins and the bioavailability of pro-angiogenic factors. The role of fibronectin and tenascin-C networks in tumor angiogenesis and metastasis will be described. We will elaborate on lessons learned about their role in vessel function from the functional ablation or the ectopic expression of both molecules. We will also elaborate on potential mechanisms of how fibronectin and tenascin-C affect cell adhesion and signaling that are relevant to angiogenesis.

The Raf/Mek/Erk signaling pathway, activated downstream of Ras primarily to promote proliferation, represents the best studied of the evolutionary conserved MAPK cascades. The investigation of the pathway has continued unabated since its discovery roughly 30 years ago. In the last decade, however, the identification of unexpected in vivo functions of pathway components, as well as the discovery of Raf mutations in human cancer, the ensuing quest for inhibitors, and the efforts to understand their mechanism of action, have boosted interest tremendously. From this large body of work, protein–protein interaction has emerged as a recurrent, crucial theme. This review focuses on the role of protein complexes in the regulation of the Raf/Mek/Erk pathway and in its cross-talk with other signaling cascades. Mapping these interactions and finding a way of exploiting them for therapeutic purposes is one of the challenges of future molecule-targeted therapy.

SummaryCellular fibronectin (cFN) variants harboring extra FN type 3 repeats, namely extra domains B and A, are major constituents of the extracellular matrix around newly forming blood vessels during development and angiogenesis. Their expression is induced by angiogenic stimuli and their assembly into fibrillar arrays is driven by cell-generated tension at 51 integrin-based adhesions. Here, we examined the role and functional redundancy of cFN variants in cultured endothelial cells by isoform-selective RNA interference. We show that FN fibrillogenesis is a cell-autonomous process whereby basally directed secretion and assembly of cellular FN are tightly coupled events that play an important role not only in signaling at cell-matrix adhesions but also at cell-cell contacts. Silencing of cFN variants differentially affects integrin usage, cell spreading, motility and capillary morphogenesis in vitro. cFN-deficient cells undergo a switch from 51-to v3-based adhesion, accompanied by a Src-regulated disruption of adherens junctions. These studies identify a crucial role for autocrine FN in subendothelial matrix assembly and junctional integrity that provides spatially and temporally restricted control of endothelial plasticity during angiogenic blood vessel remodeling.