Two of the major proteins secreted by the prostate epithelium secretory cells are PSA (prostate-specific antigen) and PSAP (prostatic-specific acid phosphatase). The molecules involved in the secretory machinery of PSA and PSAP, and the regulation of this machinery, remain unknown. In the present paper, we provide evidence that JFC1 [synaptotagmin-like protein (slp1)], a Rab27a- and PtdIns(3,4,5)P3-binding protein, regulates the androgen-dependent secretion of PSAP and PSA in human LNCaP prostate carcinoma cells. Androgen-dependent PSAP secretion was significantly inhibited in cells that expressed the C2A domain of JFC1 [PtdIns(3,4,5)P3-binding-domain], but was unaffected by JFC1 overexpression. Conversely, PSA secretion was not inhibited by the C2A domain of JFC1. We show, using immunofluorescence analysis, that JFC1 co-localizes with PSAP, but rarely with PSA, in prostate granules, suggesting that JFC1 is part of the PSAP secretory machinery. However, PSA secretion was significantly increased in LNCaP cells that overexpressed JFC1, indicating that the secretion of PSA is susceptible to variations in the intracellular concentration of JFC1. Both PSAP and PSA secretion was increased by overexpression of wild-type Rab27a or the constitutively active Rab27aQ78L. The secretion of PSA was partially inhibited in the presence of LY294002, while the secretion of PSAP was completely abolished by the PI3K (phosphoinositide 3-kinase) inhibitor. This supports the view that PI3K plays a differential role in the secretion of prostate secretory markers. In conclusion, we present evidence that JFC1 differentially regulates the secretion of PSAP and PSA, and that Rab27a and PI3K play a central role in the exocytosis of prostate-specific markers.
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November 2005
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Research Article|
October 25 2005
The Rab27a-binding protein, JFC1, regulates androgen-dependent secretion of prostate-specific antigen and prostatic-specific acid phosphatase1
Jennifer L. Johnson;
Jennifer L. Johnson
*Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Beverly A. Ellis;
Beverly A. Ellis
*Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Deborah Noack;
Deborah Noack
*Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Miguel C. Seabra;
Miguel C. Seabra
†Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ, U.K.
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Sergio D. Catz
Sergio D. Catz
2
*Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
2To whom correspondence should be addressed (email scatz@scripps.edu).
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Publisher: Portland Press Ltd
Received:
March 07 2005
Revision Received:
June 29 2005
Accepted:
July 08 2005
Accepted Manuscript online:
July 08 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 391 (3): 699–710.
Article history
Received:
March 07 2005
Revision Received:
June 29 2005
Accepted:
July 08 2005
Accepted Manuscript online:
July 08 2005
Citation
Jennifer L. Johnson, Beverly A. Ellis, Deborah Noack, Miguel C. Seabra, Sergio D. Catz; The Rab27a-binding protein, JFC1, regulates androgen-dependent secretion of prostate-specific antigen and prostatic-specific acid phosphatase. Biochem J 1 November 2005; 391 (3): 699–710. doi: https://doi.org/10.1042/BJ20050380
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