ESYT2 (extended synaptotagmin 2) is a multi-C2 domain membrane protein that tethers the endoplasmic reticulum (ER) to the plasma membrane, forming ER-plasma membrane contact sites (EPCS) critical for cellular function 1. ESYT2 binds glycerophospholipids and participates in lipid transport mechanisms. At lipid droplet-mitochondria-ER contact sites, ESYT2 functions within a multimeric complex with ESYT1 and VAPB to facilitate fatty acid transfer for β-oxidation; deletion of ESYT2 impairs lipid droplet-derived fatty acid oxidation and causes lipotoxic stress 1. ESYT2 recognizes activated fibroblast growth factor receptor 1 (FGFR1) through a conformation-dependent mechanism independent of receptor autophosphorylation, promoting rapid receptor internalization and ERK pathway signaling 2. In T cells, the short ESYT2 isoform recruits STIM1 to ER-PM junctions to activate store-operated Ca²⁺ entry via CRAC channels, independent of membrane-tethering functions 3. ESYT2 also regulates ANO1 calcium-dependent gating through reciprocal control of junctional phospholipids at STIM1 junctions 4. While ESYT2/ESYT3 knockout mice develop normally, corresponding embryonic fibroblasts show reduced migration and stress resistance 5. Aberrant ESYT2 splicing, producing an oncogenic long isoform (E-Syt2L), promotes papillary thyroid carcinoma metastasis 6. ESYT2 variants are associated with sarcoidosis susceptibility 7.