PLEKHF2 (pleckstrin homology and FYVE domain containing 2) is a phosphoinositide-binding protein that regulates endosomal trafficking and macropinocytosis through coordinated control of membrane dynamics and actin organization. Primary Function: PLEKHF2 functions as a coincidence detector of phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns4P, localizing to early endosomes and macropinosomes 1. It promotes early endosome fusion upstream of RAB5 and facilitates endosomal cargo transport by interacting with the tethering protein EEA1 2. Mechanism: PLEKHF2 coordinates actin delamination from nascent macropinosomes, enabling their navigation through subcortical actin networks toward the cell center 1. It recruits JIP4 to macropinosomal tubulating subdomains to promote membrane recycling 3. PLEKHF2 also interacts with Akt at lysosomes in a PtdIns3P-dependent manner to induce autophagy 4. Disease Relevance: PLEKHF2 variants associate with elevated intraocular pressure, a major glaucoma risk factor 5. PLEKHF2 loci show cross-ancestral association with systemic lupus erythematosus, particularly in patients with elevated interferon-alpha 6. Additionally, peptide regions derived from PLEKHF2 demonstrate antimicrobial properties against bacterial pathogens 7. Clinical Significance: PLEKHF2's role in macropinocytosis impacts cancer cell metabolism, as KRAS-transformed cells require PLEKHF2 for protein uptake and amino acid utilization 1.