Disease relevance of HCLS1

• A role for LEDGF/p75 in targeting HIV DNA integration [1].
• Although a direct role in integration has only been demonstrated for LEDGF/p75, to date, each validated cellular co-factor for HIV-1 integration could constitute a promising new target for antiviral therapy [2].
• Deficient p75 low-affinity neurotrophin receptor expression does alter the composition of cellular infiltrate in experimental autoimmune encephalomyelitis in C57BL/6 mice [3].
• Antinuclear autoantibodies in prostate cancer: immunity to LEDGF/p75, a survival protein highly expressed in prostate tumors and cleaved during apoptosis [4].
• RESULTS: Anti-LEDGF/p75 autoantibodies were detected by ELISA in 18.4% of PCa patients and 5.5% of matched controls (P < 0.001) but not in patients with benign prostatic hyperplasia (BPH) [4].

High impact information on HCLS1

• Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened [5].
• Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain [5].
• While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed [5].
• Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity [6].
• We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable [6].

Chemical compound and disease context of HCLS1

• Exposure of SN56 cholinergic neuroblastoma cells to dibutyryl cAMP and retinoic acid for 3 days caused their morphologic differentiation along with the increase in choline acetyltransferase activity, acetylcholine content and release, calcium content, and the expression of p75 neurotrophin receptors [7].

Biological context of HCLS1

• The human HCLS1 gene maps to chromosome 3q13 by fluorescence in situ hybridization [8].
• HS1 contains 3.5 tandem repeats, a coiled-coil region, and an SH3 domain at the C terminus [9].
• Cortactin and HS1 have two clusters of potential caspase cleavage sites; one is in their actin-binding domains, and the other is close to their carboxy-terminal SH3 domains [10].
• The HS1 gene is expressed specifically in hematopoietic cells and encodes p75HS1, which carries both helix-turn-helix and Src homology 3 motifs. p75HS1 showed rapid tyrosine phosphorylation and association with a Src-like kinase, Lyn, after crosslinking of membrane-bound IgM [11].
• The amino acid sequences of five proteolytic peptides of p75, a major substrate of protein-tyrosine(s) in the signaling, showed that p75 is the human HS1 gene product [11].

Anatomical context of HCLS1

• On the other hand, deletion of the coiled-coil region abolished the ability of HS1 to bind to actin filaments and to activate the Arp2/3 complex for actin nucleation and actin branching [9].
• HS1 (hematopoietic lineage cell-specific protein 1), a substrate of protein tyrosine kinases in lymphocytes, binds to F-actin, and promotes Arp2/3 complex-mediated actin polymerization [9].
• The hematopoietic lineage cell-specific protein HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis [12].
• In this study, we examined the possible role of HS1 in the regulation of the actin cytoskeleton [13].
• Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells [14].

Associations of HCLS1 with chemical compounds

• In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme, tested in the presence of polylysine (Km = 400 nM) [15].
• Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation [16].
• Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75-dependent motor neuron apoptosis [17].
• Etanercept, a fully human soluble recombinant tumour necrosis factor p75 receptor Fc fusion protein, has been registered for the treatment of polyarticular course JIA patients who fail to respond to or do not tolerate methotrexate (MTX) [18].
• In the case of the phenolphthalein-induced group, the expression of p75 was positive in the submucosal nerve plexus but was positive in the myenteric plexus of three rats only [19].

Physical interactions of HCLS1

• A screen for HPK1 binding proteins identified the hematopoietic cell-specific protein 1 (HS1) as a potential HPK1 interaction partner [20].
• Furthermore, recombinant HS1 binds directly to Arp2/3 complex with an equilibrium dissociation constant (K(d)) of 880 nM [13].

Regulatory relationships of HCLS1

• The coiled-coil domain is required for HS1 to bind to F-actin and activate Arp2/3 complex [9].
• These data indicate the possibility that regulation of HS1 may also be under the control of Ser/Thr phosphorylation, and suggest that in quiescent cells CK2 could play a role in inducing constitutive Tyr phosphorylation of HS1 in the absence of stimuli that activate the protein tyrosine kinase pathway [15].
• We report the first evidence that HS1 is also expressed in a variety of tissues different from hematopoietic tissues by using sensitive expression analysis including real-time quantitative RT-PCR [21].

Other interactions of HCLS1

• These data suggest that the HS1 coiled-coil region acts synergistically with the repeat domain in the modulation of the Arp2/3 complex-mediated actin polymerization [9].
• HAX-1 was first identified as a protein that associates with HS1, a target of non-receptor protein tyrosine kinases within haematopoietic cells [22].
• Here we report the identification of pp105 as alpha-actinin-1, pp81 as the murine equivalent of the HS1 gene product, and pp76 as Hsc70 [23].
• Normal lung tissue showed a high degree of HS1 expression, second to the expression of hematopoietic cells [21].
• In fact, it has been shown that in isolated erythrocyte membranes, both phospho-HS1 peptide and its chimeric derivative greatly affect either the SH2-mediated recruitment of the c-Fgr to the transmembrane protein band 3 and the following phosphorylation of the protein catalyzed by the Src-like kinase c-Fgr [24].

Analytical, diagnostic and therapeutic context of HCLS1

• Fluorescence in situ hybridization using a 2.0-kb cDNA and an 8.0-kb genomic DNA clone of HCLS1 as probes revealed that the gene maps to 3q13 [8].
• Blockage of binding to p75 receptor neutralized nerve-growth-factor-induced cell death, as measured by immunoassays detecting the presence of cytosolic oligonucleosomes and by TUNEL assay to visualize DNA fragmentation [25].
• Methods p75 Neurotrophin receptor and tyrosine kinase B receptor expression was demonstrated by using FACS analysis and immunohistochemistry [26].
• Apoptotic cleavage of LEDGF/p75 was detected by immunoblotting [4].
• Here we show the occurrence of physical association between HS1 and CK2alpha as judged from both far Western blot and plasmon resonance (BIAcore) analysis [27].

References