IGSF10 is a RET antagonist regulating Ewing sarcoma growth and GnRH neuron migration

Cell Rep. 2025 Aug 26;44(8):116025. doi: 10.1016/j.celrep.2025.116025. Epub 2025 Jul 22.

Abstract

RET is a receptor tyrosine kinase that plays important roles in development, cancers, and Parkinson's disease. Here, we identify immunoglobulin superfamily member 10 (IGSF10) as a RET antagonist. We show that Ewing sarcoma depends on IGSF10 and that IGSF10 prevents RET-mediated activation of cdc42, a Rho family G protein and a key regulator of Ewing sarcoma growth as well as cell migration. We demonstrate that IGSF10 binds RET and GAS1, a cell surface RET inhibitor, and assembles an inhibitory RET-GAS1 complex, preventing a stimulatory RET-GFRA complex. IGSF10 mutations are associated with delayed puberty, and IGSF10 is shown to be necessary for the proper migration of gonadotropin-releasing hormone (GnRH) neurons. We show that the IGSF10-RET-GAS1-cdc42 pathway regulates migration of GnRH neurons and that IGSF10 mutants linked to delayed puberty are defective in RET-cdc42 regulation. These results reveal a critical role of IGSF10 as a RET antagonist in Ewing sarcoma and GnRH neurons.

Keywords: CP: Cancer; CP: Neuroscience; Ewing sarcoma; GAS1; GnRH neuron; IGSF10; RET; proteomics; secretome.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Gonadotropin-Releasing Hormone* / metabolism
  • Humans
  • Immunoglobulins* / genetics
  • Immunoglobulins* / metabolism
  • Mice
  • Neurons* / metabolism
  • Neurons* / pathology
  • Proto-Oncogene Proteins c-ret* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-ret* / genetics
  • Proto-Oncogene Proteins c-ret* / metabolism
  • Sarcoma, Ewing* / genetics
  • Sarcoma, Ewing* / metabolism
  • Sarcoma, Ewing* / pathology
  • Signal Transduction
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • Gonadotropin-Releasing Hormone
  • Proto-Oncogene Proteins c-ret
  • cdc42 GTP-Binding Protein
  • Immunoglobulins