Cell Reports: IGSF10 is a RET antagonist regulating Ewing sarcoma growth and GnRH neuron migration (Chen, Houghton, & Shiio Lab)

Panneerselvam Jayabal¹ ∙ Xiuye Ma¹ ∙ Maleeha Akram² ∙ Hannah Bow² ∙ Pranay Mandal² ∙ Naira Mansano² ∙ Yidong Chen^1,3,4 ∙ Susan T. Weintraub^4,5 ∙ Peter J. Houghton^1,4,6 ∙ Susan Wray² ∙ Yuzuru Shiio

Highlights

Ewing sarcoma depends on IGSF10, which inhibits the RET receptor tyrosine kinase
IGSF10 assembles an inhibitory RET-GAS1 complex and suppresses cdc42
The IGSF10-RET-GAS1-cdc42 pathway regulates the migration of GnRH neurons
IGSF10 mutants linked to delayed puberty are defective in RET-cdc42 regulation

Summary

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 to RET and GAS1, a cell surface RET inhibitor, and assembles an inhibitory RET-GAS1 complex, thereby preventing the formation of 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.

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