TY - JOUR
T1 - HIP1 and HIP1r Stabilize Receptor Tyrosine Kinases and Bind 3-Phosphoinositides Via Epsin N-terminal Homology Domains
AU - Hyun, Teresa S.
AU - Rao, Dinesh S.
AU - Saint-Dic, Djenann
AU - Michael, L. Evan
AU - Kumar, Priti D.
AU - Bradley, Sarah V.
AU - Mizukami, Ikuko F.
AU - Oravecz-Wilson, Katherine I.
AU - Ross, Theodora S.
PY - 2004/4/2
Y1 - 2004/4/2
N2 - 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/ΔE, 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.
AB - 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/ΔE, 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.
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U2 - 10.1074/jbc.M312645200
DO - 10.1074/jbc.M312645200
M3 - Article
C2 - 14732715
AN - SCOPUS:1642631895
SN - 0021-9258
VL - 279
SP - 14294
EP - 14306
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -