title: Plexin-B1 signalling promotes androgen receptor translocation to the nucleus.
abstract: Semaphorins and their receptors plexins have diverse roles in many cancers affecting tumour growth, metastasis and angiogenesis. Plexin-B1, the receptor for semaphorin4D (Sema4D), has been implicated in prostate cancer where mutation of the gene and overexpression of the protein occur. It is not clear, however, as to which of the several Sema4D-activated signalling pathways downstream of plexin-B1 function in prostate cancer progression. We show here that Sema4D/plexin-B1 increases the expression of androgen-responsive genes and activates the transcriptional activity of the androgen receptor (AR). Activation of plexin-B1 results in phosphorylation of AR at Serine 81, a site that is phosphorylated by nuclear kinases. Cell fractionation and immunocytochemistry studies demonstrated that the proportion of cells with AR in the nucleus increases significantly upon Sema4D treatment. The N-terminal (AF-1) domain of AR, which contains binding sites for transcription regulators, is not required for this response. Depletion of AR suppressed Sema4D-induced anchorage-independent growth of LNCaP and LNCaP-LN3 cells, demonstrating the functional significance of these findings. These results show that Sema4D/plexin-B1 signalling promotes the translocation of AR to the nucleus and thereby enhances AR transcriptional activity. Plexin-B1 is therefore a promising target for cancer therapy, especially in low androgen situations such as those imposed by androgen deprivation therapy.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Williamson
authors.affiliation: Translational Uro-Oncology Group, Division of Surgery & Interventional Science, University College London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: de Winter
authors.affiliation: Prostate Cancer Research Centre, University College London, London, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Masters
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D015870:Gene Expression; D018734:Genes, erbB-2; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface; D039961:Semaphorins