Disease relevance of HAVCR1

• The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190/4 [1].
• To characterize havcr-1 and define region(s) involved in HAV receptor function, we expressed the TSP-rich region in Escherichia coli fused to glutathione S-transferase and generated antibodies (Ab) in rabbits (anti-GST2 Ab) [1].
• CONCLUSION: Our results showed that hHAVcr-1 blocks differentiation of proximal tubule epithelial cells and that it could be used as a target for therapy of kidney carcinomas [2].
• Genetic Association Studies between the T Cell Immunoglobulin Mucin (TIM) Gene Locus and Childhood Atopic Dermatitis [3].
• Water-soluble ingredients of the herbal medicine sho-saiko-to dose-dependently inhibited the proliferation of a human hepatocellular carcinoma cell line (KIM-1) and a cholangiocarcinoma cell line (KMC-1) [4].
• NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome [5].

High impact information on HAVCR1

• One such molecule is LFA-1, which enhances the avidity of interactions between T cells and antigen-presenting cells, and is possibly involved in signal transduction across the T-cell membrane [6].
• Genomic association of the TIM family and polymorphisms in both Tim-1 and Tim-3 in different immune-mediated diseases suggest that the family may have an important role in regulating immunity, both in terms of normal immune responses and in diseases like autoimmunity and asthma [7].
• These results explain the divergent immune functions described for the murine receptors and the role of TIM-1 as a cell adhesion receptor in renal regeneration and cancer [8].
• Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein [9].
• This is a novel property of the T cell membrane form of TNF-alpha [10].

Chemical compound and disease context of HAVCR1

• Reactivity of antisera to endogenous primate retrovirus with a human T cell membrane protein: recognition of a nonviral glycoprotein by antibodies directed only against carbohydrate components [11].
• It has been found that ASTA Z 7557 does not alter the expression of Fc gamma-F- or Fc gamma-I-receptors on the T-cell membrane nor does it exhibit differential toxicity for either T-cell subpopulation [12].
• T-cell membrane-associated serine protease, tryptase TL2, binds human immunodeficiency virus type 1 gp120 and cleaves the third-variable-domain loop of gp120. Neutralizing antibodies of human immunodeficiency virus type 1 inhibit cleavage of gp120 [13].

Biological context of HAVCR1

• These features suggest that patterns of variation in HAVCR1 have been shaped by both positive and balancing natural selection in the course of primate evolution [14].
• We describe the generation of 10 monoclonal antibodies against the extracellular domain of human KIM-1, the mapping of their binding sites, and their use in identifying various forms of the protein [15].
• The extracellular domain of KIM-1 is composed of an immunoglobulin-like domain topping a long mucin-like domain, a structure that points to a possible role in cell adhesion by homology to several known adhesion proteins [15].
• Two splice variants (a and b), of the human KIM-1 having identical extracellular domains, differ in their cytoplasmic domains and tissue distributions [15].
• Nucleotide sequence analysis revealed that the amplified liver and kidney huHAVcr-1 cDNAs were identical and that they coded for a 359-amino-acid glycoprotein, termed huhavcr-1, which was approximately 79% identical to havcr-1 [16].

Anatomical context of HAVCR1

• We show that human KIM-1b is expressed in adult kidney cell lines, and we demonstrate that a soluble form of KIM-1 is shed constitutively into the culture medium of the cell lines expressing endogenous or recombinant KIM-1b by membrane-proximal cleavage [15].
• KIM-1 (kidney injury molecule-1) is a type I transmembrane glycoprotein expressed on dedifferentiated renal proximal tubule epithelial cells undergoing regeneration after toxic or ischemic injury [15].
• We propose that the shedding of KIM-1 in the kidney undergoing regeneration constitutes an active mechanism allowing dedifferentiated regenerating cells to scatter on denuded patches of the basement membrane and reconstitute a continuous epithelial layer [15].
• Hepatitis A virus receptor (HAVcr-1) and T-cell immunoglobulin- and mucin-domain-containing molecule (TIM)-3 were recently implicated as asthma susceptibility genes in the study of congenic mice [17].
• A member of Tim family, TIM-1, is considered as a membrane protein that is associated with the development of Th2 biased immune responses and may be selectively expressed on Th2 cells [18].

Associations of HAVCR1 with chemical compounds

• Release of soluble KIM-1 is enhanced by activating the cells with phorbol 12-myristate 13-acetate and can be inhibited with two metalloproteinase inhibitors, BB-94 (Batimastat) and GM6001 (Ilomastat), suggesting that the cleavage is mediated by a metalloproteinase [15].
• These results indicate that the Cys-rich region of havcr-1 and its first N-glycosylation site are required for binding of protective MAb 190/4 and HAV receptor function [1].
• Treatment of AGMK and cr5 cells with tunicamycin reduced binding of protective monoclonal Ab (MAb) 190/4, which suggested that N-glycans are required for binding of MAb 190/4 to havcr-1 [1].
• Fifty % effective doses on day 3 of exposure to sho-saiko-to were 353.5 +/- 32.4 micrograms/ml for KIM-1 and 236.3 +/- 26.5 micrograms/ml for KMC-1 [4].
• The addition of insulin increased the growth rate of all examined cell lines and partially inhibited the AFP secretion in those cell lines except KIM-1/c-4, while the addition of dexamethasone inhibited the growth and stimulated the AFP secretion in all of the cell lines [19].

Physical interactions of HAVCR1

• Taken together, these data show that the activation of PKCtheta by the TCR and CD28 plays an important role in the assembly and activation of IKK complexes in the T cell membrane [20].
• Beta 2-microglobulin-bound T-cell membrane components containing both human TL-like antigens and HLA(A, B, C) antigens were partially purified from Renex 30-solubilized membrane material of cells of a human T-cell-type leukemia cell line, HPB-ALL [21].

Regulatory relationships of HAVCR1

• Furthermore, T cell membrane TNF-alpha was shown to be one of the contact-mediated signals regulating monocyte IL-10 production [22].
• The specificity of the hrlL-2-induced response was defined in experiments in which mitogenicity of this T cell growth-promoting lymphokine was completely abrogated by blocking the T cell membrane receptor for IL-2 with the anti-Tac monoclonal antibody [23].
• Recent studies have determined that the expression of a novel, 39 kD, T-cell membrane protein is responsible for inducing T-cell-dependent B-cell activation [24].
• Anti-TNF-alpha mAb inhibited the T cell membrane-induced MMP-9 release, indicating a possible autocrine regulation of MMP release by mast cell TNF-alpha [25].

Other interactions of HAVCR1

• Conclusions: In addition to confirming the importance of genetic variation in TIM-1, our results also suggest that genetic variants in the ligand for TIM-1, TIM-4, also contribute to the presentation of AD and related disorders [3].
• Tim-1 (HUGO designation HAVCR1) polymorphisms have been linked to the regulation of atopy in mice and humans, suggestive of a role in immune regulation [26].
• Third, levels of divergence among human, chimp, and gorilla sequences were unusually high in HAVCR1-exon 4 sequences [14].
• Contact with T cells modulates monocyte IL-10 production: role of T cell membrane TNF-alpha [22].
• Ligation of the T cell membrane antigen CD28 strongly enhances cytokine secretion in human T lymphocytes that are activated via T cell receptor (TcR)/CD3 or CD2 molecules [27].

Analytical, diagnostic and therapeutic context of HAVCR1

• Western blot analysis with anti-GST2 Ab detected 62- and 65-kDa bands in AGMK cells and 59-, 62-, and 65-kDa bands in dog cells transfected with the HAVcr-1 cDNA (cr5 cells) but not in dog cells transfected with the vector alone (DR2 cells) [1].
• METHODS: This work reports on the identification of human hepatitis A virus cellular receptor 1 (hHAVcr-1) as a differentially expressed gene in ccRCC using RNA-based arbitrarily primed polymerase chain reaction (RAP-PCR) [2].
• Analysis of eluted material by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing, and two-dimensional electrophoresis demonstrated the major proteins to be of Mr 56,000, pI 4.8-5.1 and Mr 60,000, pI 5.0-5.6, and these were radiolabeled, indicating an origin in part from the T-cell membrane [28].
• Forty renal cell carcinoma (RCC) and 484 nonrenal tumors were analyzed by immunohistochemistry for expression of hKIM-1 (group 1) [29].
• Tissue was examined for expression of hKIM-1, and cell-free urine supernatants were analyzed for hKIM-1 by ELISA [29].

References