In mice and humans, there are two known members of the Huntingtin interacting protein 1 (HIP1) family, HIP1 and HIP1-related (HIP1r). Based on structural and functional data, these proteins participate in the clathrin trafficking network. The inactivation of Hip1 in mice leads to spinal, hematopoietic, and testicular defects. To investigate the biological function of HIP1r, we generated a Hip1r mutant allele in mice. Hip1r homozygous mutant mice are viable and fertile without obvious morphological abnormalities. In addition, embryonic fibroblasts derived from these mice do not have gross abnormalities in survival, proliferation, or clathrin trafficking pathways. Altogether, this demonstrates that HIP1r is not necessary for normal development of the embryo or for normal adulthood and suggests that HIP1 or other functionally related members of the clathrin trafficking network can compensate for HIP1r absence. To test the latter, we generated mice deficient in both HIP1 and HIP1r. These mice have accelerated development of abnormalities seen in Hip1 -deficient mice, including kypholordosis and growth defects. The severity of the Hip1r/Hip1 double-knockout phenotype compared to the Hip1 knockout indicates that HIP1r partially compensates for HIP1 function in the absence of HIP1 expression, providing strong evidence that HIP1 and HIP1r have overlapping roles in vivo.Huntingtin interacting protein 1-related (HIP1r) was originally identified in 1998 due to its homology to Huntingtin interacting protein 1 (HIP1) (24) . The yeast orthologue of HIP1 and HIP1r, Sla2p, is necessary for endocytosis, proper cytoskeletal function, and growth at high temperatures (9, 30). Both HIP1 and HIP1r have been implicated in endocytosis or trafficking of clathrin-coated vesicles. Domains shared between HIP1 and HIP1r include the epsin N-terminal homology (ENTH) domain, a central coiled-coil region containing a leucine zipper, and a carboxyl-terminal TALIN homology domain. TALIN is an actin-binding protein implicated in both cell-substratum and cell-cell interactions (23).The ENTH domains bind inositol lipids and have thus far only been found in endocytic proteins. The founding mammalian members of the group of proteins with ENTH domains are epsin, AP180, and CALM. ENTH domains bind the plasma membrane lipid, phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P 2 ), and have well-established roles in clathrin-mediated endocytosis (7, 11). In contrast, the ENTH domains of HIP1 and HIP1r preferentially bind the intracellular membrane lipids, phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P 2 ) and phosphatidylinositol-3,5-bisphosphate (PtdIns-3,4-P 2 ) (10). This suggests that the HIP1 family may have distinct functions associated with intracellular trafficking in addition to their roles in clathrin-mediated receptor internalization. In fact, recent evidence points toward different functions at a molecular level for the ENTH domain of epsin 1 versus that of AP180 (more recently referred to as the ANTH domain). In the case of epsin, the EN...

Huntingtin-interacting protein 1 (HIP1) is frequently overexpressed in prostate cancer. HIP1 is a clathrin-binding protein involved in growth factor receptor trafficking that transforms fibroblasts by prolonging the half-life of growth factor receptors. In addition to human cancers, HIP1 is also overexpressed in prostate tumors from the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. Here we provide evidence that HIP1 plays an important role in mouse tumor development, as tumor formation in the TRAMP mice was impaired in the Hip1 null/null background. In addition, we report that autoantibodies to HIP1 developed in the sera of TRAMP mice with prostate cancer as well as in the sera from human prostate cancer patients. This led to the development of an anti-HIP1 serum test in humans that had a similar sensitivity and specificity to the anti-A-methylacyl CoA racemase (AMACR) and prostate-specific antigen tests for prostate cancer and when combined with the anti-AMACR test yielded a specificity of 97%. These data suggest that HIP1 plays a functional role in tumorigenesis and that a positive HIP1 autoantibody test may be an important serum marker of prostate cancer. (Cancer Res 2005; 65(10): 4126-33)

Up to half of all patients with necrotizing enterocolitis require acute surgical treatment. Determining when to operate on these patients can be challenging. Utilizing a combination of clinical and metabolic indicators, we sought to identify the optimal timing of surgical intervention. A retrospective chart review was conducted on patients with necrotizing enterocolitis from 2001 to 2010. Previously validated clinical (abdominal erythema, palpable abdominal mass, hypotension), radiographic (pneumoperitoneum, portal venous gas, fixed bowel loop, severe pneumatosis intestinalis), and laboratory (acidosis, bacteremia, hyponatremia, bandemia, neutropenia, thrombocytopenia) indicators were assessed for the ability to predict the need for acute surgical intervention as a simple indicator score, based on the sum of the indicators listed above. A total of 197 patients were included. One hundred and twenty-four procedures (28 peritoneal drains, 96 laparotomy) were performed on 122 patients (62%). Median indicator score was 4 (range: 0–8). Logistic regression identified abdominal erythema (odds ratio [OR] = 3.3, P = 0.001), acidosis (OR = 2.6, P = 0.004), and hypotension (OR = 1.9, P = 0.05) as independently associated with surgical intervention. A significant increase in surgical intervention was noted for patients with indicator score of 3 or more. In conclusion, if three or more indicators exist, operative intervention is very likely required. In the absence of pneumoperitoneum, abdominal erythema, acidosis, and hypotension are especially important.

The results can be used to develop better robotic control algorithms that will be more responsive to surgeons' needs. Copyright © 2015 John Wiley & Sons, Ltd.