Plexin-B1 mutations in prostate cancer

Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19040-5. doi: 10.1073/pnas.0702544104. Epub 2007 Nov 16.

Abstract

Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / secondary
  • Bone Neoplasms / genetics
  • Bone Neoplasms / secondary
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphatic Metastasis / genetics
  • Male
  • Mutation, Missense*
  • Neoplasm Invasiveness / genetics
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / physiology
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / physiology
  • Polymorphism, Single-Stranded Conformational
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Protein Structure, Tertiary
  • Pseudopodia / ultrastructure
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / physiology
  • Signal Transduction
  • rac1 GTP-Binding Protein / metabolism
  • ras Proteins / metabolism

Substances

  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • RAC1 protein, human
  • Receptors, Cell Surface
  • RRAS protein, human
  • rac1 GTP-Binding Protein
  • ras Proteins