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The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors.

VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.

Pubmed ID: 18555774


  • Tsuda H
  • Han SM
  • Yang Y
  • Tong C
  • Lin YQ
  • Mohan K
  • Haueter C
  • Zoghbi A
  • Harati Y
  • Kwan J
  • Miller MA
  • Bellen HJ



Publication Data

June 13, 2008

Associated Grants

  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cell Line
  • Drosophila Proteins
  • Drosophila melanogaster
  • Endoplasmic Reticulum
  • Humans
  • Ligands
  • Membrane Proteins
  • Protein Folding
  • Protein Structure, Tertiary
  • Receptors, Eph Family
  • Ubiquitination
  • Vesicular Transport Proteins