Vascular Endothelial Growth Factor (VEGF) Receptor Signaling

Students enrolled in Dr. Dan Sem's Biological Chemistry course at Marquette University in spring of 2011 worked in teams to model six proteins involved in the VEGF signaling pathway leading to angiogenesis. Since angiogenesis is essential for providing vasculature to growing tumors, inhibiting these proteins is one focus of chemotherapy. In addition to learning the role that their team's protein played in the signaling cascade, teams were asked to design a potential inhibitor of their protein. All models were built to the same scale, and on the last day of class, Dr. Sem reviewed the VEGF signal transduction pathway using the models. Students piped in with specific structural details of their proteins, and protein-protein interactions were demonstrated using the models.

Elise Span, one of the students enrolled in Dr. Sem's course, subsequently worked with Dr. David Goodsell to create a cellular landscape to illustrate VEGF signal transduction. Elise identified proteins involved in the pathway utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG), followed by reviewing primary literature and discussions with researchers at the Medical College of Wisconsin who study this pathway. Elise compiled important information about each protein in the pathway (size, shape, interactions/functions, PDB ID numbers), from which Dr. Goodsell made a series of iterative sketches involving researcher input. The final molecular landscape is a 16x30" watercolor painting that hangs outside the CBM and reproduced below.

(a) Simulated electron micrograph showing two cells from the vascular endothelium. The size and location of the portion depicted in the painting is shown in color. (b) The final molecular landscape depicting VEGF signaling. Blood serum in tan at upper left. The adherens junction between two cells in yellow-green at left. The cytoplasm is in turquoise, and the nuclear pore is at the center in green. The nucleus is at the right in blues and purples.

(a) VEGF signaling. VEGF-A (1) in blood serum binds to VEGFR (2) and causes it to dimerize. This activates the kinase domains inside the cell. Two downstream pathways are shown. In one, C-src (3) is phosphorylated, causing it to open up and phosphorylate cadherins (4) in adherens junctions, releasing alpha-catenin (6), which dimerizes and bundles actin (beta-catenin (5), which is involved in the adherens junction structure, is also shown). In the other pathway, the receptor initiates a cascade of phosphorylation reactions through PLC-gamma (7), PKC (8), Raf-1 (9), MEK (10), and ultimately ERK-2 (11). ERK-2 is transported through the nuclear pore (the large structure at the center of the full painting, not depicted here). (b) In the nucleus, ERK-2 (11) phosphorylates C-fos (12), causing it to form a heterodimer with Jun (13) and become active as a transcription factor effecting transcription. It is shown here in an enhancer binding to the transcription mediator (14) and RNA polymerase (15). Finally, DUSP5 (16) terminates the process by dephosphorylating ERK-2.

For more information about the development of the Angiogenesis Molecular Landscape, see:

Span, Elise A., Goodsell, David S., Ramchandran, Ramani, Franzen, Margaret A., Herman, Tim and Sem, Daniel S. 2013. Protein Structure in Context: The Molecular Landscape of Angiogenesis. Biochemisty and Molecular Biology Education 41(4):213-223.

The CREST Project is funded by NSF-DUE 1022793 and NSF-DUE 1323414.

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