Other entities represented in this entry:
HGNC Approved Gene Symbol: HIP1
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:75,533,298-75,738,941 (from NCBI)
The HIP1 gene encodes huntingtin interacting protein-1, which is an endocytic protein that colocalizes with the adaptor complex AP2 (see, e.g., AP2A1; 601026) and clathrin to play a role in endocytosis at the plasma membrane of various cells (summary by Metzler et al., 2003).
Huntington disease (HD; 143100) may be due to a toxic gain-of-function caused by abnormal protein-protein interactions related to the elongated polyglutamine sequence of huntingtin (HTT; 613004). Thus, the binding of distinct proteins to the polyglutamine region could either confer a new property on huntingtin or alter its normal interactions with other proteins. Wanker et al. (1997) hypothesized that the specific binding of a protein with a restricted pattern of expression to the elongated polyglutamine stretch of the huntingtin protein could cause selective vulnerability to particular cells. The potential huntingtin-interacting proteins that have been identified include huntingtin-associated protein-1 (600947), the glycolytic enzyme GAPD (138400), and the ubiquitin-conjugating enzyme E2-25K, also named HIP2 (602846), which binds selectively to the N terminus of huntingtin. Wanker et al. (1997) demonstrated the specific binding of a protein to the N terminus of huntingtin, both in the yeast 2-hybrid screen and in in vitro binding experiments. A protein region downstream of the polyglutamine stretch in huntingtin was essential for the interaction in vitro. Thus, the authors designated the new protein 'huntingtin-interacting protein-1' (HIP1). The HIP1 cDNA isolated by the 2-hybrid screen encodes a 55-kD fragment of the novel protein. Using an affinity-purified polyclonal antibody raised against recombinant HIP1, a protein of 116 kD was detected in brain extracts by Western blot analysis. The predicted amino acid sequence of the HIP1 fragment exhibited significant similarity to cytoskeleton proteins, suggesting to Wanker et al. (1997) that HIP1 and huntingtin play a functional role in the cell filament network. The HIP1 gene was found to be ubiquitously expressed at low levels in different brain regions. HIP1 is enriched in human brain but can also be detected in other human tissues, as well as in mouse brain. The authors noted that HIP1 and huntingtin behave almost identically during subcellular fractionation and both proteins are enriched in the membrane-containing fractions.
Chopra et al. (2000) determined that the HIP1 gene contains 32 exons spanning approximately 215 kb of genomic DNA and gives rise to 2 alternative splice forms, termed HIP1-1 and HIP1-2, which differ in their 5-prime sequence. HIP1-1 encodes a deduced 1,034-amino acid protein, and HIP1-2 a deduced 1,003-amino acid protein.
To confirm the localization of HIP1 to the same region as Williams-Beuren syndrome (WBS; 194050), Wedemeyer et al. (1997) mapped ELN and HIP1 in a radiation hybrid (RH) panel. HIP1 was found to be located 2.03 cR proximal to elastin (ELN; 130160) in the RH mapping panel; the calculated distance between the 2 loci was 200 to 400 kb. Although this suggested that the HIP1 locus is within the region of WBS deletion, this was found not to be the case when somatic cell hybrids in which the deleted and nondeleted chromosome 7 from a typical Williams syndrome patient had been separated were typed.
Kalchman et al. (1997) assigned the HIP1 gene to human chromosome 7q11.2 by FISH. By radiation hybrid analysis, Wedemeyer et al. (1997) mapped the HIP1 gene to 17q11.23. Himmelbauer et al. (1998) mapped the mouse Hip1 gene to chromosome 5.
Kalchman et al. (1997) showed that HIP1 is a membrane-associated protein that colocalizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in S. cerevisiae. The huntingtin-HIP1 interaction was restricted to the brain and correlated inversely with the polyglutamine length in huntingtin. Their results provided a molecular link between huntingtin and the neuronal cytoskeleton and suggested that, in Huntington disease, loss of normal huntingtin-HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.
Hackam et al. (2000) found that overexpression of HIP1 in a human neuronal precursor cell line resulted in caspase-3 (600636)-dependent activation of the intrinsic apoptosis pathway. They identified a domain within HIP1 that showed homology to the death effector domain (DED) found in proteins involved in apoptosis. Expression of the HIP1 DED domain alone resulted in cell death indistinguishable from that induced by full-length HIP1. The substitution of a conserved phenylalanine within the DED domain eliminated HIP1 toxicity.
Waelter et al. (2001) identified 3 HIP1-associated proteins, clathrin heavy chain (CLTC; 118955) and alpha-adaptin A and C (AP2A1; 601026). In vitro binding studies revealed that the central coiled-coil domain is required for the interaction of HIP1 with clathrin, whereas DPF-like motifs located upstream to this domain are important for the binding of HIP1 to the C-terminal 'appendage' domain of alpha-adaptin A and C. Expression of full-length HIP1 in mammalian cells resulted in a punctate cytoplasmic immunostaining characteristic of clathrin-coated vesicles. In contrast, when a truncated HIP1 protein containing both the DPF-like motifs and the coiled-coil domain was overexpressed, large perinuclear vesicle-like structures containing HIP1, huntingtin, clathrin, and endocytosed transferrin were observed, suggesting that HIP1 is an endocytic protein, the structural integrity of which may be crucial for maintenance of normal vesicle size in vivo.
Gervais et al. (2002) found that HIP1 binds to the HIP1 protein interactor (HIPPI; 606621), which has partial sequence homology to HIP1 and similar tissue and subcellular distribution. The availability of free HIP1 is modulated by polyglutamine length within huntingtin, with disease-associated polyglutamine expansion favoring the formation of proapoptotic HIPPI-HIP1 heterodimers. This heterodimer can recruit procaspase-8 (601763) into a complex of HIPPI, HIP1, and procaspase-8, and launch apoptosis through components of the extrinsic cell death pathway. Gervais et al. (2002) proposed that huntingtin polyglutamine expansion liberates HIP1 so that it can form a caspase-8 recruitment complex with HIPPI, possibly contributing to neuronal death in Huntington disease.
Rao et al. (2002) found that HIP1 is expressed in prostate and colon tumor cells, but not in corresponding benign epithelia. They investigated the relationship between HIP1 expression in primary prostate cancer and clinical outcomes with tissue microarrays. HIP1 expression was significantly associated with prostate cancer progression and metastasis. Conversely, primary prostate cancers lacking HIP1 expression consistently showed no progression after radical prostatectomy. In addition, the expression of HIP1 was elevated in prostate tumors from the transgenic mouse model of prostate cancer. At the molecular level, expression of a dominant-negative mutant of HIP1 led to caspase-9 (602234)-dependent apoptosis, suggesting that HIP1 is a cellular survival factor. Thus, HIP1 may play a role in tumorigenesis by allowing the survival of precancerous or cancerous cells. HIP1 might accomplish this via regulation of clathrin-mediated trafficking, a fundamental cellular pathway that had not theretofore been associated with tumorigenesis. HIP1 represents a putative prognostic factor for prostate cancer and a potential therapy target in prostate as well as colon cancers.
In a patient with chronic myelomonocytic leukemia (CMML; see 607785) with a t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the HIP1 gene to the platelet-derived growth factor-beta receptor gene (PDGFRB; 173410). They identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFRB gene. The reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein product was a 180-kD protein when expressed in a murine hematopoietic cell line and was constitutively tyrosine phosphorylated. Furthermore, the fusion gene transformed the same mouse hematopoietic cell line to interleukin-3-independent growth.
Metzler et al. (2003) found that Hip1-null mice showed failure to thrive and developed a neurologic phenotype by 3 months of age manifest as tremor and gait ataxia secondary to a rigid thoracolumbar kyphosis. The phenotype was progressive, resulting in premature death. The defect did not result from anomalies of the skeleton, muscle, or neuromuscular junction, and there were no morphologic changes in the central nervous system. Liposomal membranes isolated from mutant mouse brains showed decreased assembly of endocytic protein complexes, likely resulting in impaired clathrin vesicle formation. Primary neurons from wildtype mice showed Hip1 immunostaining in dendrites and cell bodies, suggesting Hip1 involvement in postsynaptic endocytic events. Following AMPA stimulation, Hip1 colocalized with GluR1 (138248)-containing AMPA receptors and became concentrated in cell bodies, indicating its role in receptor trafficking. Neurons from the Hip1-null mice showed significantly impaired clathrin-mediated internalization of GluR1-containing AMPA receptors. The findings indicated that HIP1 regulates AMPA receptor trafficking in the central nervous system via its function in clathrin-mediated endocytosis.
Oravecz-Wilson et al. (2004) reported that 3 different mutations of murine Hip1 lead to hematopoietic abnormalities, reflected by diminished early progenitor frequencies and resistance to 5-FU-induced bone marrow toxicity. Two of the Hip1 mutant lines also displayed the spinal defects, including kypholordosis, described by Metzler et al. (2003). The authors concluded that, in addition to being required for the survival/proliferation of cancer cells and germline progenitors, HIP1 is also required for the survival/proliferation of diverse types of somatic cells, including hematopoietic progenitors.
Bradley et al. (2007) found that Hip1/Hip1r (605613) double-knockout mice were dwarfed, had severe vertebral defects, and died in early adulthood. However, these phenotypes were not observed in single Hip1- or Hip1r-null mice, suggesting that the 2 genes can compensate for one another. Studies did not show abnormalities in endocrine function or growth factor receptors. Embryonic fibroblasts from Hip1/Hip1r double-knockout mice showed delayed growth and delayed progression through the cell cycle, but no increase in apoptosis. Expression of human HIP1 rescued many aspects of the double-knockout phenotype, suggesting that the human and mouse proteins share some functions.
Komoike et al. (2010) identified and cloned the zebrafish Hip1 gene. Knockdown of the gene resulted in absence of yolk extension, a narrow body along the dorsoventral axis, and mandibular hypoplasia, but no other significant abnormalities were noted.
Bradley, S. V., Hyun, T. S., Oravecz-Wilson, K. I., Li, L., Waldorff, E. I., Ermilov, A. N., Goldstein, S. A., Zhang, C. X., Drubin, D. G., Varela, K., Parlow, A., Dlugosz, A. A., Ross, T. S. Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1. Hum. Molec. Genet. 16: 1279-1292, 2007. [PubMed: 17452370] [Full Text: https://doi.org/10.1093/hmg/ddm076]
Chopra, V. S., Metzler, M., Rasper, D. M., Engqvist-Goldstein, A. E. Y., Singaraja, R., Gan, L., Fichter, K. M., McCutcheon, K., Drubin, D., Nicholson, D. W., Hayden, M. R. HIP12 is a non-proapoptotic member of a gene family including HIP1, an interacting protein with huntingtin. Mammalian Genome 11: 1006-1015, 2000. [PubMed: 11063258] [Full Text: https://doi.org/10.1007/s003350010195]
Gervais, F. G., Singaraja, R., Xanthoudakis, S., Gutekunst, C.-A., Leavitt, B. R., Metzler, M., Hackam, A. S., Tam, J., Vaillancourt, J. P., Houtzager, V., Rasper, D. M., Roy, S., Hayden, M. R., Nicholson, D. W. Recruitment and activation of caspase-8 by the huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nature Cell Biol. 4: 95-105, 2002. [PubMed: 11788820] [Full Text: https://doi.org/10.1038/ncb735]
Hackam, A. S., Yassa, A. S., Singaraja, R., Metzler, M., Gutekunst, C.-A., Gan, L., Warby, S., Wellington, C. L., Vaillancourt, J., Chen, N., Gervais, F. G., Raymond, L., Nicholson, D. W., Hayden, M. R. Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. J. Biol. Chem. 275: 41299-41308, 2000. [PubMed: 11007801] [Full Text: https://doi.org/10.1074/jbc.M008408200]
Himmelbauer, H., Wedemeyer, N., Haaf, T., Wanker, E. E., Schalkwyk, L. C., Lehrach, H. IRS-PCR-based genetic mapping of the huntingtin interacting protein gene (HIP1) on mouse chromosome 5. Mammalian Genome 9: 26-31, 1998. [PubMed: 9434941] [Full Text: https://doi.org/10.1007/s003359900674]
Kalchman, M. A., Koide, H. B., McCutcheon, K., Graham, R. K., Nichol, K., Nishiyama, K., Kazemi-Esfarjani, P., Lynn, F. C., Wellington, C., Metzler, M., Goldberg, Y. P., Kanazawa, I., Gietz, R. D., Hayden, M. R. HIP1, a human homologue of S. cerevisiae Slap2, interacts with membrane-associated huntingtin in the brain. Nature Genet. 16: 44-53, 1997. [PubMed: 9140394] [Full Text: https://doi.org/10.1038/ng0597-44]
Komoike, Y., Fujii, K., Nishimura, A., Hiraki, Y., Hayashidani, M., Shimojima, K., Nishizawa, T., Higashi, K., Yasukawa, K., Saitsu, H., Miyake, N., Mizuguchi, T., Matsumoto, N., Osawa, M., Kohno, Y., Higashinakagawa, T., Yamamoto, T. Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly. Genesis 48: 233-243, 2010. [PubMed: 20146355] [Full Text: https://doi.org/10.1002/dvg.20607]
Metzler, M., Li, B., Gan, L., Georgiou, J., Gutekunst, C.-A., Wang, Y., Torre, E., Devon, R. S., Oh, R., Legendre-Guillemin, V., Rich, M., Alvarez, C., Gertsenstein, M., McPherson, P. S., Nagy, A., Wang, Y. T., Roder, J. C., Raymond, L. A., Hayden, M. R. Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking. EMBO J. 22: 3254-3266, 2003. [PubMed: 12839988] [Full Text: https://doi.org/10.1093/emboj/cdg334]
Oravecz-Wilson, K. I., Kiel, M. J., Li, L., Rao, D. S., Saint-Dic, D., Kumar, P. D., Provot, M. M., Hankenson, K. D., Reddy, V. N., Lieberman, A. P., Morrison, S. J., Ross, T. S. Huntingtin interacting protein 1 mutations lead to abnormal hematopoiesis, spinal defects and cataracts. Hum. Molec. Genet. 13: 851-867, 2004. [PubMed: 14998932] [Full Text: https://doi.org/10.1093/hmg/ddh102]
Rao, D. S., Hyun, T. S., Kumar, P. D., Mizukami, I. F., Rubin, M. A., Lucas, P. C., Sanda, M. G., Ross, T. S. Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J. Clin. Invest. 110: 351-360, 2002. [PubMed: 12163454] [Full Text: https://doi.org/10.1172/JCI15529]
Ross, T. S., Bernard, O. A., Berger, R., Gilliland, D. G. Fusion of huntingtin interacting protein 1 to platelet-derived growth factor-beta receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91: 4419-4426, 1998. [PubMed: 9616134]
Waelter, S., Scherzinger, E., Hasenbank, R., Nordhoff, E., Lurz, R., Goehler, H., Gauss, C., Sathasivam, K., Bates, G. P., Lehrach, H., Wanker, E. E. The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. Hum. Molec. Genet. 10: 1807-1817, 2001. [PubMed: 11532990] [Full Text: https://doi.org/10.1093/hmg/10.17.1807]
Wanker, E. E., Rovira, C., Scherzinger, E., Hasenbank, R., Walter, S., Tait, D., Colicelli, J., Lehrach, H. HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum. Molec. Genet. 6: 487-495, 1997. [PubMed: 9147654] [Full Text: https://doi.org/10.1093/hmg/6.3.487]
Wedemeyer, N., Peoples, R., Himmelbauer, H., Lehrach, H., Francke, U., Wanker, E. E. Localization of the human HIP1 gene close to the elastin (ELN) locus on 7q11.23. Genomics 46: 313-315, 1997. [PubMed: 9417924] [Full Text: https://doi.org/10.1006/geno.1997.5027]