Disease relevance of HSH2D

• The adaptor protein HSH2 attenuates apoptosis in response to ligation of the B cell antigen receptor complex on the B lymphoma cell line, WEHI-231 [1].
• This review presents historical and clinical information on the rare human brain disorder known as Alexander disease (ALX), and reports on the recent discovery of the gene that appears to be causative [2].
• Insonation of cell suspensions prepared in previously insonated HSA + ALX fluid produced about 0.4% hemolysis; this also differed significantly from the controls [3].

High impact information on HSH2D

• Lipoxin A(4) (LXA(4)), ATL, and their metabolic stable analogs elicit cellular responses and regulate leukocyte trafficking in vivo by activating the specific receptor, ALX [4].
• ALX at the level of DNA has sequence homology to the N-formylpeptide receptor and as an orphan GPCR was initially referred to as the N-formylpeptide receptor-like 1 [4].
• Although LXA(4) is the endogenous potent ligand for ALX activation, a number of peptides can also activate this receptor to stimulate calcium mobilization and chemotaxis in vitro [4].
• Together, these findings indicate that injured bronchial epithelial cells up-regulate ALX in a COX-2-dependent manner to promote LXA(4)-mediated resolution of airway inflammation [5].
• The carboxyl-terminal segment of the adaptor protein ALX directs its nuclear export during T cell activation [6].

Biological context of HSH2D

• Nuclear import of ALX also depends on its carboxyl-terminal segment [6].
• We found that the ALX SH2 domain is both necessary and sufficient to mediate inhibition of RE/AP activation [7].
• Mutation of the SH2 domain did not affect ALX expression, relative localization in the cytoplasm and nucleus, phosphorylation, or a mobility shift in response to TCR signaling alone [7].
• The ALX Src homology 2 domain is both necessary and sufficient to inhibit T cell receptor/CD28-mediated up-regulation of RE/AP [7].
• To understand how ALX functions downstream of CD28, we generated a panel of site-directed mutants as well as truncations in which potential protein-binding sites were mutated or absent [7].

Anatomical context of HSH2D

• Expression of the adaptor protein hematopoietic Src homology 2 (HSH2) was found to significantly decrease BCR-mediated apoptosis in the murine WEHI-231 cell line [1].
• To elucidate the interaction of glucocorticoids and lipoxin A(4) for anti-inflammation, we analyzed in vitro expression of lipoxin A(4) receptor (ALX) on human neutrophils and the in vivo anti-inflammatory effect of glucocorticoids and LXA(4) using a dermal inflammation mouse model [8].
• Lipoxin A4 biology in the human synovium. Role of the ALX signaling pathways in modulation of inflammatory arthritis [9].
• Analyses of the lipid-derived mediators from exudates using LC-MS tandem mass spectroscopy indicated an altered profile in hALX transgenic mice that included lower levels of LTB4 and increased amounts of lipoxin A4 compared with nontransgenic littermates [10].
• The hALX transgenic mice gave markedly decreased PMN infiltrates to the peritoneum with zymosan and altered the dynamics of this response [10].

Associations of HSH2D with chemical compounds

• Hence, we postulate that HSH2 functions as an adapter protein involved in tyrosine kinase signaling, and possibly regulates cytokine signaling and cytoskeletal reorganization, in hematopoietic cells [11].
• Here it is shown that this depletion occurs via nuclear export of ALX, which depends on a leucine-rich nuclear export signal (NES) in its carboxyl segment and on the CRM-1 transport protein [6].
• ALX contains several sites for potential protein-protein interaction, including an Src homology 2 (SH2) domain, four PXXP polyproline sequences, and two likely sites of tyrosine phosphorylation [7].
• Both LXA4 and 15-epi-LXA4 interact with the LXA4 receptor (ALX) to mediate anti-inflammatory actions [12].
• ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter [13].

Analytical, diagnostic and therapeutic context of HSH2D

• Analysis of signal transduction pathways activated in response to BCR ligation revealed that HSH2 does not significantly alter total protein tyrosine phosphorylation or Ca2+ mobilization [1].
• This work is now being extended as a diagnostic test, as well as to seek understanding of the pathogenesis of ALX and possible approaches for treatment [2].
• Some insonation regimens also involved the inclusion of Albunex (ALX; an ultrasound microbubble contrast agent) to enhance ultrasound-induced inertial cavitation [14].

References