KBTBD2 is a substrate adaptor of the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that primarily regulates insulin and insulin-like growth factor signaling pathways 1. The protein functions by recruiting phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1/p85α) to the CRL3 complex, where p85α undergoes K48-linked polyubiquitination and proteasomal degradation 2. In adipocytes, this degradation enhances insulin sensitivity by limiting p85α abundance [UniProt]. Beyond metabolic regulation, KBTBD2 plays a critical role in bone development by controlling osteoblast differentiation through IGF-1 signaling; loss of KBTBD2 impairs osteogenic differentiation and skeletal growth 1. Mutations impairing KBTBD2 function have clinical significance in SHORT syndrome, a genetic disorder characterized by short stature, where the p.(Arg649Trp) mutation in p85α reduces its binding to KBTBD2, disrupting IGF-1-mediated AKT activation 1. Recent evidence identifies KBTBD2 as a novel autosomal recessive developmental disorder-associated gene 3, and genome-wide Mendelian randomization analysis suggests it as a potential therapeutic target for childhood asthma 4. KBTBD2 also interacts with ezrin in a Src kinase-dependent manner 5, indicating broader cellular signaling roles.