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First published online 9 January 2008
doi: 10.1242/dev.009910

Development 135, 775-784 (2008)
Published by The Company of Biologists 2008
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Role of epithelial cell fibroblast growth factor receptor substrate 2{alpha} in prostate development, regeneration and tumorigenesis

Yongyou Zhang1,*, Jue Zhang1,*, Yongshun Lin1, Yongsheng Lan1, Chunhong Lin1, Jim W. Xuan2, Michael M. Shen3, Wallace L. McKeehan1, Norman M. Greenberg4 and Fen Wang1,{dagger}

1 Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030-3303, USA.
2 Department of Surgery, University of Western Ontario, London, ON, N6A 4G5, Canada.
3 Departments of Medicine, and Genetics and Development, Columbia University, College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, Room 217B, New York, NY 10032, USA.
4 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, WA 98109-1024, USA.

{dagger} Author for correspondence (e-mail: fwang{at}ibt.tmc.edu)

Accepted 24 November 2007

The fibroblast growth factor (FGF) regulates a broad spectrum of biological activities by activation of transmembrane FGF receptor (FGFR) tyrosine kinases and their coupled intracellular signaling pathways. FGF receptor substrate 2{alpha} (FRS2{alpha}) is an FGFR interactive adaptor protein that links multiple signaling pathways to the activated FGFR kinase. We previously showed that FGFR2 in the prostate epithelium is important for branching morphogenesis and for the acquisition of the androgen responsiveness. Here we show in mice that FRS2{alpha} is uniformly expressed in the epithelial cells of developing prostates, whereas it is expressed only in basal cells of the mature prostate epithelium. However, expression of FRS2{alpha} was apparent in luminal epithelial cells of regenerating prostates and prostate tumors. To investigate FRS2{alpha} function in the prostate, the Frs2{alpha} alleles were ablated specifically in the prostatic epithelial precursor cells during prostate development. Similar to the ablation of Fgfr2, ablation of Frs2{alpha} disrupted MAP kinase activation, impaired prostatic ductal branching morphogenesis and compromised cell proliferation. Unlike the Fgfr2 ablation, disrupting Frs2{alpha} had no effect on the response of the prostate to androgens. More importantly, ablation of Frs2{alpha} inhibited prostatic tumorigenesis induced by oncogenic viral proteins. The results suggest that FRS2{alpha}-mediated signals in prostate epithelial cells promote branching morphogenesis and proliferation, and that aberrant activation of FRS2-linked pathways might promote tumorigenesis. Thus, the prostate-specific Frs2{alpha}cn mice provide a useful animal model for scrutinizing the molecular mechanisms underlying prostatic development and tumorigenesis.

Key words: Adaptor proteins, Growth factors, Receptor tyrosine kinases, Prostate cancer, Mouse models






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