KIDINS220 (kinase D-interacting substrate 220) is a neurotrophin-responsive membrane protein that integrates signaling from growth factor receptors to coordinate neuronal development and survival. Structurally, it contains ankyrin repeats, transmembrane domains, and PDZ-binding motifs, positioning it as a docking hub for signaling complexes. Mechanistically, KIDINS220 promotes sustained mitogen-activated protein kinase signaling downstream of neurotrophins by recruiting the CRKL-C3G complex and activating Rap1-dependent ERK phosphorylation; it also facilitates NGF-induced recruitment of RAPGEF2 to late endosomes and supports ephrin-mediated axon guidance through syntrophin-dependent receptor localization. Beyond neurodevelopment, KIDINS220 regulates phosphate homeostasis as an essential binding partner of the phosphate exporter XPR1, enabling its proper cellular localization and substrate-dependent activation in response to inositol pyrophosphates. Disease relevance spans neurodevelopmental and neurodegenerative conditions: heterozygous KIDINS220 variants cause SINO syndrome (spastic paraplegia, intellectual disability, nystagmus, obesity), presenting with developmental delay and brain ventricular dilatation in most cases 1. KIDINS220 accumulates abnormally in Alzheimer's disease brain tissue, correlating with impaired neurotrophin signaling 2. Additionally, the XPR1-KIDINS220 complex represents a therapeutic vulnerability in ovarian and uterine cancers, where phosphate dysregulation can be exploited to trigger cell death 3, though targeted inhibitors of this pathway remain in preclinical development.