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(Chest. 2005;128:577S.)
© 2005 American College of Chest Physicians

Mts1/S100A4 Stimulates Human Pulmonary Artery Smooth Muscle Cell Migration Through Multiple Signaling Pathways*

Edda Spiekerkoetter, MD; Allan Lawrie, PhD; Sandra Merklinger, PhD; Noona Ambartsumian, PhD; Eugene Lukanidin, PhD; Ann-Marie Schmidt, MD and Marlene Rabinovitch, MD

* From the Department of Pediatrics (Drs. Spiekerkoetter, Lawrie, Merklinger, and Rabinovitch), Stanford University School of Medicine, Palo Alto, CA; the Department of Molecular Cancer Biology (Drs. Ambartsumian and Lukanidin), Institute of Cancer Biology, The Danish Cancer Society, Copenhagen, Denmark; and the Department of Physiology, Medicine and Surgery (Dr. Schmidt), Columbia University, New York, NY.

Correspondence to: Edda Spiekerkoetter, MD, Department of Pediatrics, Stanford University, 269 Campus Dr, CCSR Room 2245, Stanford, CA 94305; e-mail: eddas{at}stanford.edu

Mice that overexpress the gene Mts1/S100A4 develop a plexogenic arteriopathy that is similar to that observed in patients with idiopathic pulmonary hypertension. We have shown that recombinant Mts1 stimulates smooth muscle cell migration likely through the receptor for advanced glycation end products (RAGE). The objective of the present study was to delineate the intracellular signaling pathways involved in concert with signaling through bone morphogenetic protein (BMP) receptor-II. Human pulmonary arterial smooth muscle cells were either treated with recombinant Mts1 (500 ng/mL) or BMP-2 (10 ng/mL), or were preincubated with inhibitors of different signaling pathways (eg, janus activating kinase [JAK] 2, extracellular signal-regulated kinase [ERK]1/2, c-Jun n-terminal kinase, or p38) as well as both soluble RAGE (sRAGE) and a RAGE-blocking antibody. Migration was assessed in a modified Boyden chamber. The phosphorylation status of the above signaling molecules, including Rac, was assessed by Western immunoblotting of human pulmonary arterial smooth muscle cell lysates. Mts1 increased migration twofold (n = 15; p < 0.001) in association with the activation of Rac, p38, and JAK2. This response was suppressed by preincubation with sRAGE and the RAGE-blocking antibody, and by the JAK2, ERK1/2, p38, and c-Jun n-terminal kinase inhibitors (n = 9 per group). The phosphorylation of ERK1/2 was inhibited by the ERK inhibitor and was reduced by the RAGE antibody but not by the sRAGE. BMP2 also showed a twofold induction of migration (n = 6; p < 0.001) and was associated with the activation of p38 and ERK1/2. Our studies suggest that the migratory response to Mts1 involves a coordinated program of intracellular signaling potentially involving at least two receptors and multiple cross-activating pathways that may include interaction with BMPR-II signaling.


   Footnotes
 
Abbreviations: ERK = extracellular signal-regulated kinase; JAK = janus activating kinase; RAGE = receptor for advanced glycation end products; sRAGE = soluble receptor for advanced glycation end products





This Article
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