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| Isoform 1 is a single-pass type I membrane protein, have a length of 371 aa. Protein sequence includes four main regions: FN3 (Fibronectin type 3), encompassed from 109 to 207 aa; WSXWS motif, encompassed from 200 to 204 aa; Box 1 motif encompassed from 261 to 269 aa; Transmembrane region encompassed from 232 to 252 aa. Isoform 2 is a secreted protein an only have FN3 region, encompassed from 7 to 76 aa. |
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Description | CRLF2 gene encodes a member of the type I cytokine receptor family. CRLF2 has three protein coding transcripts: CRLF2-201, CRLF2-202, CRLF2-203 and CRLF2-204. CRLF2-203 and CRLF2-201 transcript variants generate the longer isoform of 371 amino acids (42 kDa), also called isoform 1. Isoform 1 has the protein regions that characterize this family gene: FN3 (Fibronectin type 3) region, WSXWS motif, Box 1 motif, and transmembrane region. Post-translational modifications of CRLF2 protein include glycosylation at asparagine residues (Asn169, Asn55 and Asn47) and phosphorylation at isoleucine (Ile271) and tyrosine (Tyr74) residues. The other isoform, called isoform 2, is encoded by the transcript variant CRLF2-202. This isoform is shorter, 259 amino acids (26.6 kDa), at N-terminus compared with isoform 1 because lacks an alternate exon which results in translation initiation at a downstream start codon. ENSG00000205755; UniProt Q9HC73, Q9HC73-2, Q4V300; neXtProt NX_Q9HC73 |
Expression | CRLF2 protein is present in intestine, bone marrow, spleen, thymus, and is more abundant in dendritic cells. neXtProt NX_Q9HC73 |
Localisation | CRLF2 isoform 1 is a cell membrane protein and CRLF2 isoform 2 is a secreted protein. |
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| A) TSLP /CRLF2/ IL7R complex activation is implicated in Th2 differentiation. TSLP binds to CRLF2/IL-7Rα heterodimer in dendritic cells and promotes the expression of OX40 ligand ( TNFSF4 (CD252)) and IL13, IL5, IL4 and TNF to induce Th2 differentiation. B) TSLP/CRLF2/IL-7Rα complex activation in dendritic cells. Activation of CRLF2 was described by first time in dendritic cells. This scheme exemplifies the main nodes involved. |
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Function | CRLF2 forms a functional complex with IL-7Rα (IL-7 receptor α chain) and TSLP (thymic stromal lymphopoietin). Functional complex activation induces different signals depending on the type of cell and also exerts multiple functions. Heterocomplex is involved in a plethora of physiologic and pathologic immune functions, including: tolerance, allergy, autoimmune diseases and cancer. (Tsilingin et al., 2017). CRLF2 is expressed mainly in dendritic cells and also hematopoietic cells including T cells, B cells, granulocytes, and mast cells. Heterocomplex main function is the differentiation to T helper type 2 (Th2) cells. CRLF2-activated dendritic cells express OX40 ligand and trigger naive CD4+ to differentiate into inflammatory Th2 cells and the expansion of allergen-specific Th2 memory cells (Lin et al., 2018). According with phosphoproteome analysis in diverse cell types, after TSLP binds to the CRLF2/IL-7Rα heterocomplex, the phosphorylation of Janus kinase1 ( JAK1) and 2 ( JAK2) activates signal transducers and activators of transcription (STATs) proteins, including: STAT1, STAT3, STAT4, STAT5A, STAT5B and STAT6. Heterocomplex also activates other signaling molecules such as PI3K/AKT/MTOR pathway, SRC / TEC pathway, MAPK3 / MAPK1 (ERK1/2), NF-kB, MAPK8 / MAPK9 (JNK1 JNK2), and p38/MAPK activation (Zhong Jun et al., 2012; Zhong Jun et al., 2014). In allergy or autoimmune disease has been described high expression of TSLP and overstimulation of TSLP/CRLF2/IL-7Rα complex. Tezepelumab is a human monoclonal antibody that blocks functional complex and is successfully used in asthma treatment (Van Rompaey et al., 2012). The role of functional heterocomplex in cancer is still controversial, in certain neoplasia plays a pro-tumorigenic role, whereas in others, a protective role. For example, in cervix, breast, and pancreas cancer has been describe an increase of metastasis associated with an overstimulation of TSLP/CRLF2/IL-7Rα. On the other hand, in colon and skin carcinoma, functional heterocomplex has been associated with better prognostic. In addition to above, CRLF2 gene has genetic alterations that promote cell survival in cancer. The genetic rearrangements P2RY8/CRLF2 and IGH/CRLF2, generate CRLF2 overexpression, and the mutation Phe232Cys, encodes CRLF2 proteins capable of forming homodimers and self-activation, both described in acute lymphoblastic leukemia (Varricchi et al., 2018; Zhong Jun, 2014). |
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| C) Phosphoproteomic analysis reveals multiple targets in TSLP/CRLF2/IL-7Rα pathway in different cell types. This scheme shows experimental curated data obtained from NetSlim. |
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Homology | Table 2. CRLF2 Orthologues Name | Organism | CRLF2 | P. troglodytes | CRLF2 (ENSCAFG00000011034) | C. lupus | LOC529792 (ENSBTAG00000020242) | B. taurus | Crlf2 (ENSMUSG00000033467) | M. musculus | Crlf2 (ENSRNOG00000049828) | R. novergicus | LOC418668 (ENSGALG00000016696) | G. gallus |
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Whole-Genome Sequencing of a Family with Hereditary Pulmonary Alveolar Proteinosis Identifies a Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Disruption |
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PMID 28233860 |
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Expression and regulation of thymic stromal lymphopoietin and thymic stromal lymphopoietin receptor heterocomplex in the innate-adaptive immunity of pediatric asthma |
Lin SC, Cheng FY, Liu JJ, Ye YL |
Int J Mol Sci. 2018; 19(4) |
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Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia |
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PMID 19641190 |
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Thymic Stromal Lymphopoietin: to cut a long story short |
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PMID 28275684 |
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Virtual screening for inhibitors of the human TSLP: TSLPR interaction |
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