FRS2 (fibroblast growth factor receptor substrate 2) is an adapter protein that functions as a critical scaffolding component in receptor tyrosine kinase signaling. Functionally, FRS2 links activated FGFR and NGF receptors to downstream signaling cascades, particularly the FRS2/RAS/RAF/MEK/ERK1/2 pathway 1. It mediates phosphorylation of PIK3R1 (PI3K regulatory subunit) and modulates signaling by competing with SHC1 for binding sites on NTRK1, thereby coordinating multiple intracellular responses to growth factor stimulation. Mechanistically, FRS2 exists as two variants with distinct roles: FRS2α acts as a control center for FGFR signaling promoting tumorigenesis, while FRS2β negatively regulates EGFR signaling with potential tumor-suppressive function 2. Beyond canonical FGF signaling, endothelial FRS2 deletion exacerbates atherosclerosis progression by disrupting protective FGFR signaling and promoting endothelial-to-mesenchymal transition 3. Diseases: FRS2 alterations are clinically significant in multiple malignancies. Recurrent FRS2 amplification occurs in lung adenocarcinoma and ovarian cancer, where it functions as an oncogene 4. In retroperitoneal liposarcoma, high FRS2 expression independently predicts poor overall and disease-free survival 5. In osteosarcoma, elevated FRS2 promotes angiogenesis and poor prognosis, regulated by miR-429 and miR-206 6. FRS2 alterations also associate with improved ribociclib response in hormone receptor-positive breast cancer 7. These findings position FRS2 as both a prognostic biomarker and potential therapeutic target across cancer types.