Disease relevance of CLEC11A

• Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism [1].
• On the contrary, expression of the stem cell growth factor (c-kit ligand) was detected in all three uveal melanoma cell lines, suggesting the presence of autocrine (paracrine) stimulation pathways [2].
• SCGF levels gradually increased after SCT regardless of graft-versus-host disease or type of transplant [3].
• Lysophosphatidic acid-depleted serum, hepatocyte growth factor and stem cell growth factor stimulate colony growth of small cell lung cancer cells through a calcium-independent pathway [4].
• Neutrophil cytosol from patients with certain forms of autosomal recessive chronic granulomatous disease (CGD) lack either p47 or p67 [5].

High impact information on CLEC11A

• Recent studies, however, demonstrated that Wnt is not only a general stem cell growth factor but can also influence cell lineage decisions in certain stem cell types by promoting specific fates at the expense of others [6].
• Here, we show that the c-kit ligand (KL), a recently identified stem cell growth factor, at concentrations 10-100 times lower than that required to promote cell proliferation, enhances the release of histamine and leukotriene C4 in response to IgE receptor crosslinking of human lung MC [7].
• Although lipid X inhibited thrombin-induced phosphorylation of P47 it did not suppress secretion of [14C]serotonin, indicating the role of protein kinase C-independent pathways in platelet stimulation by thrombin [8].
• The proline-rich motif of p47 PX in the free state adopts a distorted left-handed polyproline type II helix conformation [9].
• Expression of SCGF mRNA is restricted to myeloid cells and fibroblasts, suggesting that SCGF is a growth factor functioning within the hematopoietic microenvironment [10].

Chemical compound and disease context of CLEC11A

• We have previously shown that piebaldism can result from missense and frameshift mutations of the KIT proto-oncogene, which encodes the cellular receptor tyrosine kinase for the mast/stem cell growth factor [11].

Biological context of CLEC11A

• Here we report the molecular cloning, expression, and characterization of a cDNA encoding human SCGF using a newly developed lambdaSHDM vector that is more efficient for differential and expression cloning. cDNA for SCGF encodes a 29-kDa polypeptide without N-linked glycosylation [10].
• Cloning of P47 was achieved using a CEMLAI/NP cDNA library screened with a degenerate oligonucleotide probe based on its NH2-terminal amino acid sequence [12].
• The studies of the c-kit oncogene and the stem cell growth factor in the migration and survival of the primordial germ cells to the genital ridge during development have defined at least 1 important role of growth factors in spermatogenesis [13].
• Besides, numerous cDNAs, similar to LSLCL (identity of 93-99%), are found in 'expressed sequence tags' databases from various origins, mostly fetal and undifferentiated tumour tissues [14].
• HAG increased the cytosolic ionized calcium concentration ([Ca2+]i) and stimulated protein (P47 and P20) phosphorylation, phosphatidic acid (PA) synthesis, serotonin secretion, and platelet aggregation [15].

Anatomical context of CLEC11A

• CONCLUSION: SCGF is selectively produced by osseous and hematopoietic stromal cells, and can mediate their proliferative activity on primitive hematopoietic progenitor cells [16].
• METHODS: Recombinant human (rh) SCGF-alpha was purified from a conditioned medium of SCGF-alpha gene-transfected CHO cells [16].
• A human myeloid cell line, KPB-M15, constitutively produces a novel hematopoietic cytokine, termed stem cell growth factor (SCGF), possessing species-specific proliferative activities [10].
• The KPB-M15 myeloid cell line constitutionally secreted a considerable quantity of SCGF, while other T- or myeloid-monocytoid cell lines did not secrete SCGF [17].
• A hybridoma clone (7H1) resulting from the fusion between CEMLAI/NP and human embryonic fibroblasts MRC5 cells produced very large amounts of P47 that was purified using Jacalin lectin (specific for O-glycans) and microsequenced [12].

Associations of CLEC11A with chemical compounds

• This observation suggests that patients with CGD may also have a defect in lymphocyte function. p47 protein and mRNA levels increase during retinoic acid-induced neutrophil differentiation of HL60 cells [18].
• It is not known if activation of PKC occurs with pairs of agonists, such as epinephrine and A23187, that do not individually phosphorylate p47, nor is it known what role the concentration of cytoplasmic Ca++ ([Ca++]i) plays in these events [19].
• Nuclear run-on transcription assays show that the gene for p47 is induced at the transcriptional level in a cycloheximide-insensitive manner [18].
• These results suggest that p47, but not p67, is a participant with membrane and/or other cytosol components in early arachidonate-dependent reactions [5].
• Rapid phosphorylation of a human platelet protein of Mr 40,000-47,000 (P47), a substrate for protein kinase C activation, preceded secretion of serotonin when platelets were triggered by the most active heptaacyl MLA ion, m/z 1953 [20].

Other interactions of CLEC11A

• On transfer to fresh liquid culture with VEGF and SCGF, nonadherent cells again produce an adherent and a nonadherent population [21].
• The recombinant protein was added to liquid cultures of CD34+ human marrow cells stimulated with IL-3 alone or with both IL-3 and either insulin-like growth factor II (IGF-II) or stem cell growth factor (SCF) [22].
• The largest cluster of upregulated genes included a group of genes classified as growth factors, cytokines and chemokines (e.g. interleukin-3, interleukin-4, B-cell growth factor 1 and stem cell growth factor) [23].
• SCGF could disclose some human-specific mechanisms as yet unidentified from studies on the murine hematopoietic system [10].
• Karyotypic analysis of the expanded cells from cord blood CD34(+) cells by 7-day culture with stem cell growth factor, interleukin (IL)-3, IL-6, granulocyte colony-stimulating factor, and erythropoietin was performed [24].

Analytical, diagnostic and therapeutic context of CLEC11A

• The molecule, highly purified by immunoadsorbent affinity chromatography, retained SCGF activity in vitro, e.g., erythroid burst-promoting activity and granulocyte-macrophage-colony potentiation [17].
• In this study, we have established enzyme-linked immunosorbent assay (ELISA) to quantify human SCGF and measured serum cytokines in normal volunteers and 27 patients undergoing stem cell transplantation (SCT), including six autologous and 21 allogeneic transplants [3].
• The maximum level of SCGF was observed during the rapid granulocyte recovery phase in patients subjected to an autologous transplantation, and during the granulocyte stabilization phase in allogeneic patients [3].
• The source of SCGF was further analyzed by RT-PCR and we found that SCGF was highly expressed in bone marrow (BM) CD34(+) and CD34(-)CD33(+) cells, but not in BM CD34(-)CD33(-) cells, BM stromal cells and peripheral blood cells [3].
• The high oxidase activity observed in macrophages and monocytes after the treatment with 1 alpha OHD3, correlated significantly to the increase in the amount of the cytosolic factor p47 of the NADPH oxidase as detected by western blotting analysis [25].

References