Disease relevance of Hcls1

• Two members of this family (cortactin and HS1) were differentially expressed in murine B lymphoid tumor cell lines; both were detected in plasmacytoma cell lines, however HS1 was additionally detected in pre-B lymphoma and B lymphoma cell lines [1].
• By provirus tagging, we demonstrate that the HS1 step was clonal indicating that a cell selection must occur in vivo [2].

High impact information on Hcls1

• 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 [3].
• 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 [3].
• HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed [3].
• Induction of tyrosine phosphorylation on a variety of cellular proteins, such as Vav, Cbl, and HS1, upon BCR cross-linking was also abolished in these B cells [4].
• The 75-kD HS1 protein is highly tyrosine-phosphorylated during B cell antigen receptor (BCR)-mediated signaling [5].

Chemical compound and disease context of Hcls1

• Rapid tyrosine phosphorylation of HS1 in the response of mouse lymphoma L5178Y-R cells to photodynamic treatment sensitized by the phthalocyanine Pc 4 [6].

Biological context of Hcls1

• Colocalization of HS1-green fluorescent protein with BCR was also correlated with tyrosine phosphorylation of HS1 [7].
• These data indicate that Syk plays an important role in the translocation of HS1 into lipid rafts and may be responsible for actin assembly recruitment to rafts and subsequent antigen presentations [7].
• Owing to low expression of HS1, WEHI-231-derived M1 cells, unlike the parental cells, are insensitive to BCR-mediated apoptosis [5].
• Crossing the HS1-deficient mice with the mice harboring transgenes encoding alpha and beta chains of T-cell antigen receptor against a male H-Y antigen resulted in a progeny that demonstrated a significantly impaired ability of thymic negative selection [8].
• The SH3 domain and the potential helix-turn-helix motif in LckBP1 suggest that this molecule may associate with various molecules and function as a DNA binding molecule [9].

Anatomical context of Hcls1

• Furthermore HS1 was unable to translocate into lipid rafts in a chicken B cell line deficient in Syk [7].
• Using unstimulated T lymphocytes, we further demonstrated that Lck binds to HS1 in vivo and that HS1 is tyrosine phosphorylated upon TCR stimulation [10].
• These data show that disrupting HS1 has profoundly influenced the ability of erythroid cells to terminally differentiate [11].
• The truncated HS1 also suppressed the development of erythroid colonies from fetal liver cells [11].
• HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases [12].

Associations of Hcls1 with chemical compounds

• Interestingly a murine HS1 mutant at the tyrosine residues Tyr388 and Tyr405 targeted by Syk failed to respond to BCR cross-linking for either translocation into lipid rafts or colocalization with BCR within cells [7].
• Here we show that the hemopoietic-specific protein HS1 interacted directly with the SH3 domain of Lyn, via its proline-rich region [11].
• Hydrocortisone-free cultures also synthesized heparan sulfate (HS) proteoglycans, including a cell-associated form (HS1), partially excluded from the TSK-400 column, and a secretory form (HS2), eluting at Kd = 0.15 [13].
• Several distinct F-actin/PIP2-binding proteins, such as gelsolin, which severs and caps the plus-ends of actin filaments, or HS1, which cross-links actin filaments, have been shown to suppress v-Ha-Ras-induced malignant transformation when they are overexpressed [14].

Physical interactions of Hcls1

• HS1 interacts with Lyn and is critical for erythropoietin-induced differentiation of erythroid cells [11].

Other interactions of Hcls1

• We previously identified a gene, LckBP1, which encodes a protein that binds to the Lck SH3 domain and is identical to murine SH1 [10].
• Distinct binding patterns of HS1 to the Src SH2 and SH3 domains reflect possible mechanisms of recruitment and activation of downstream molecules [10].
• In two of five such escapees, alterations in either Syk, HS1, and/or Lyn were observed [15].
• A truncated HS1, bearing the Lyn-binding domain, was introduced into J2E erythroleukemic cells to determine the impact upon responsiveness to erythropoietin [11].

Analytical, diagnostic and therapeutic context of Hcls1

• The development of lymphoid cells in HS1-deficient mice, generated through gene targeting, appeared normal [8].
• HS1BP3 associates with HS1 proteins in vivo as confirmed by immunoprecipitation in B and T cell lines [16].
• Molecular cloning and characterization of mouse HS1 [17].
• Sequence analysis of the mouse HS1 cDNA revealed that it is highly homologous to human HS1 (total percent match = 84%) especially in the amino-terminal half, which contains unique repeating motifs, and in the carboxyl-terminal Src-homology 3 domain [17].
• Based on molecular characterization, parasite morphology, serologic reactivity, histology, and immunohistochemistry, HS1 was indistinguishable from S. neurona, and HS2 was indistinguishable from T. gondii [18].

References