Plexin-B1 signalling promotes androgen receptor translocation to the nucleus

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 cle...

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Bibliographic Details
Published in:Oncogene 2016-02, Vol.35 (8), p.1066-1072
Main Authors: Williamson, M, de Winter, P, Masters, J R
Format: Article
Language:English
Subjects:
Androgen receptors
Androgens
Angiogenesis
Antigens, CD - metabolism
Binding sites
Cancer
Carcinogenesis
Cell Nucleus - metabolism
Cellular signal transduction
Gene Expression
Genes, erbB-2
Genetic aspects
Genetic research
Health aspects
Hormone receptors
Humans
Immunocytochemistry
Kinases
Male
Metastases
Nerve Tissue Proteins - metabolism
Phosphorylation
Properties
Prostate cancer
Prostatic Neoplasms - metabolism
Protein expression
Receptors, Androgen - metabolism
Receptors, Cell Surface - metabolism
Semaphorins
Semaphorins - metabolism
Signal Transduction
Transcription
Translocation (Genetics)
Tumor Cells, Cultured
Tumors
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.160