The receptor tyrosine kinase (RTK) pathway plays an essential role in development
and disease by controlling cell proliferation and differentiation. Here, we profile
the Drosophila larval brain by single-cell RNA-sequencing and identify Amalgam (Ama),
which encodes a cell adhesion protein of the immunoglobulin IgLON family, as regulating
the RTK pathway activity during glial cell development. Depletion of Ama reduces cell
proliferation, affects glial cell type composition and disrupts the blood-brain barrier
(BBB), which leads to hemocyte infiltration and neuronal death. We show that Ama depletion
lowers RTK activity by upregulating Sprouty (Sty), a negative regulator of the RTK
pathway. Knockdown of Ama blocks oncogenic RTK signaling activation in the Drosophila
glioma model and halts malignant transformation. Finally, knockdown of a human ortholog
of Ama, LSAMP, results in upregulation of SPROUTY2 in glioblastoma cell lines, suggesting
that the relationship between Ama and Sty is conserved.
