title: HIP1 and HIP1r stabilize receptor tyrosine kinases and bind 3-phosphoinositides via epsin N-terminal homology domains.
abstract: Huntingtin-interacting protein 1-related (HIP1r) is the only known mammalian relative of huntingtin-interacting protein 1 (HIP1), a protein that transforms fibroblasts via undefined mechanisms. Here we demonstrate that both HIP1r and HIP1 bind inositol lipids via their epsin N-terminal homology (ENTH) domains. In contrast to other ENTH domain-containing proteins, lipid binding is preferential to the 3-phosphate-containing inositol lipids, phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,5-bisphosphate. Furthermore, the HIP1r ENTH domain, like that of HIP1, is necessary for lipid binding, and expression of an ENTH domain-deletion mutant, HIP1r/deltaE, induces apoptosis. Consistent with the ability of HIP1r and HIP1 to affect cell survival, full-length HIP1 and HIP1r stabilize pools of growth factor receptors by prolonging their half-life following ligand-induced endocytosis. Although HIP1r and HIP1 display only a partially overlapping pattern of protein interactions, these data suggest that both proteins share a functional homology by binding 3-phosphorylated inositol lipids and stabilizing receptor tyrosine kinases in a fashion that may contribute to their ability to alter cell growth and survival.
authors.affiliation: Department of Internal Medicine, Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Hyun
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
authors.forename: Djenann
authors.initials: D
authors.lastname: Saint-Dic
authors.forename: L Evan
authors.initials: LE
authors.lastname: Michael
authors.forename: Priti D
authors.initials: PD
authors.lastname: Kumar
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Bradley
authors.forename: Ikuko F
authors.initials: IF
authors.lastname: Mizukami
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Oravecz-Wilson
authors.forename: Theodora S
authors.initials: TS
authors.lastname: Ross
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000911:Antibodies, Monoclonal; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002966:Clathrin / Q000378:metabolism; D004268:DNA-Binding Proteins; D004705:Endocytosis / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007294:Inositol / Q000378:metabolism; D007700:Kinetics; D008840:Microfilament Proteins; D016296:Mutagenesis; D009479:Neuropeptides / Q000235:genetics*; D010716:Phosphatidylinositols / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D002966:Clathrin; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; C489537:HIP1R protein, human; D008840:Microfilament Proteins; D009479:Neuropeptides; D010716:Phosphatidylinositols; D033921:Vesicular Transport Proteins; C114154:epsin; D007294:Inositol; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases