www.landesbioscience.com Cell Cycle 1991

Epidermal growth factor receptor (EGFR) is highly expressed or overly active in many types of cancer, including head and neck, breast, ovarian, esophageal and non-small cell lung cancers.1 Increased expression of EGFR has been associated with resistance to standard therapies and poor patient prognosis. EGFR signaling promotes can-cer progression by stimulating angiogen-esis, cancer cell proliferation, migration, invasion and metastasis. To design more efficient anti-EGFR therapies for cancers, the mechanisms by which EGFR expres-sion and signaling are modulated must be well defined. Phosphoinositides control EGFR sig-naling during the endocytosis, endosomal sorting and lysosomal degradation of EGFR.2,3 It is well established that PI4,5P 2 is abundant at the plasma membrane and is required for clathrin-dependent endocy-tosis of membrane receptors,4 while PI3P is abundant at endosomal membranes, where it recruits PI3P binding proteins that are essential in endosomal sorting of receptors.4 Though PI4,5P 2 is pres-ent at endosomes, its role in endosomal sorting is unexpected and was largely ignored in previous work. Recently, we have demonstrated that type Igamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5), an enzyme that generates PI4,5P 2, is targeted to endosomes and is required for the endosomal sorting and lysosomal degradation of EGFR.5 These findings challenge the dogma that PI4,5P 2 primarily functions in endocytosis, while PI3P controls endosomal sorting. PIPKIγ is a major enzyme that syn-thesizes PI4,5P 2 in the cell.6 Six PIPKIγ An unexpected role for PI4,5P2 in EGF receptor endosomal traffickin