CRLF2 (Cytokine receptor like factor 2)

Alias (NCBI)	CRL2
	TSLPR
HGNC (Hugo)	CRLF2
HGNC Alias symb	CRL2
	TSLPR
Atlas_Id	51262
Location	Xp22.33 and Yp11.2, negative strand. ENSG00000205755  [Link to chromosome band Xp22]
Location_base_pair	Starts at 1190490 and ends at 1212649 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CRLF2.png]
Local_order	CRLF2 is located on chromosome X and Y, on the short arm and lies between RPL14P5 (ribosomal protein L4 pseudogene 5) and CSF2RA (colony stimulating factor 2 receptor alpha subunit). Entrez Gene ID: 64109
	A) Chromosomal location of CRLF2 gene. B) Mapping of CRLF2 gene and local order on genomic context of the chromosome X and Y.
	Chromosomes obtained from MHH-CALL-4 cell line positive to IGH/CRLF2 translocation detected by fluorescence in situ hybridization (FISH). The der(Y) chromosome is lost in the cell line. Metaphase hybridized with CRLF2 break-apart probe (Cytocell Aquarius) with a normal chromosome X (green-red signal, yellow arrow), and der(14) (green signal, white arrow).

	CRLF2 gene encodes four transcript variants: two with 8 exons, one with 9 exons, and one with 7 exons (exons are represented by violet boxes and introns by black line). ENSG00000205755, Entrez Gene ID: 64109
Description	CRLF2 gene is located in reverse strand of pseudo-autosomal region 1 (PAR1) in X and Y chromosomes. CRLF2 encompasses 22kb of DNA and give rise to four transcript variants with different lengths: 1.6, 1.5, 1.0 and 1.7 kb. ENSG00000205755
Transcription	CRLF2 gene encodes a member of type I cytokine receptor family and generate four transcript variants (Table 1). Three generate protein coding transcripts and one generates a non-sense mediated decay transcript. According with gene expression array data CRLF2 is expressed, from highest to lowest, in: cervix > lung > bladder > small intestine > esophagus > stomach > skin > prostate > uterus > vagina > testes > colon > spleen > mammary gland > thyroid > whole blood. It has been reported that in pathological conditions the transcription rate of CRLF2 is altered. CRLF2 overexpression (fold change > 2) is found in: microbial infection, immunodeficiency syndromes (X-linked hyper IgM syndrome), autoimmune diseases (arthritis), and cancer (esophagus dysplasia, papillary thyroid carcinoma and acute lymphoblastic leukemia). The CRLF2 subexpression (fold change < 2) has been reported only in cancer (myelodysplastic syndrome, non-small cell lung carcinoma, hepatobiliary carcinoma, colorectal carcinoma, pancreatic adenocarcinoma and breast carcinoma). ENSG00000205755; UniProt Q9HC73; neXtProt NX_Q9HC73 Table 1. Transcript variants and proteins Name (RefSeq) Exons   Coding Exons   Transcript Length   Protein Length   Type of transcript CRLF2-203 (NM_022148)    8 8 1, 639 bp 371 residues Protein coding CRLF2-201 9   8 1, 545 bp 371 residues Protein coding CRLF2-202 (NM_001012288)   7 6 1, 013 bp 259 residues Protein coding CRLF2-204 (NR_110830)   8 5 1, 789 bp 232 residues Non-sense mediated decay

	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.
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.
	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.
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).
	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.
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

	Mutations in CRLF2 have been identified in a wide range of cancer types. Most of them are missense mutations (green), nonsense mutations are also represented (violet).
Somatic	Table 3 CRLF2 mutations in cancer CDS Mutation   Cancer Type Type of Mutation c.315C>A Bladder Carcinoma Missense mutation c.357C>A Bladder Carcinoma Missense mutation c.193G>A Bladder Carcinoma Missense mutation c.89T>A Bladder Carcinoma Missense mutation c.33C>G Diffuse Large B Cell Lymphoma Missense mutation c.415T>C Diffuse Large B Cell Lymphoma Missense mutation c.349C>T Osteosarcoma Missense mutation c.330T>C Colon Carcinoma Missense mutation c.384G>A Colon Carcinoma Missense mutation c.33C>G Colon Carcinoma Missense mutation c.159G>A Rectum Carcinoma Missense mutation c.474C>T Adenocarcinoma Missense mutation c.372C>T Adenocarcinoma Missense mutation c.411G>A Adenocarcinoma Missense mutation c.603C>T Adenocarcinoma Missense mutation c.405G>A Adenocarcinoma Missense mutation c.669G>A Adenocarcinoma Missense mutation c.642T>C Adenocarcinoma Missense mutation c.642T>C Endometrioid Carcinoma Missense mutation c.321C>T Lung Carcinoma Missense mutation c.384G>A Pleura Carcinoma Missense mutation c.456C>T Melanoma Missense mutation c.411G>A Melanoma Missense mutation c.468C>T Melanoma Missense mutation c.123C>T Melanoma Missense mutation c.630G>A Melanoma Missense mutation c.534G>A Melanoma Missense mutation c.438C>T Melanoma Missense mutation c.383C>T Merkel Cell Carcinoma Missense mutation c-.335G>T Merkel Cell Carcinoma Missense mutation c.604G>A Urinary Tract Carcinoma Missense mutation c.742C>A Urinary Tract Carcinoma Missense mutation c.208C>A Neuroblastoma Missense mutation c.139A>T Glioma Missense mutation c.404C>T Glioma Missense mutation c.365C>T Glioma Missense mutation c.598C>A Glioma Missense mutation c.404C>T Glioma Missense mutation c.313C>T Glioma Missense mutation c.74G>A Glioma Missense mutation c.632G>A Glioma Missense mutation c.445G>A Meningioma Missense mutation c.660G>T Breast Carcinoma Missense mutation c.734C>T Breast Carcinoma Missense mutation c.526G>C Breast Carcinoma Missense mutation c.297C>G Cervix Carcinoma Missense mutation c.658G>C Cervix Carcinoma Missense mutation c.566C>T Endometrium Carcinoma Missense mutation c.536A>T Endometrium Carcinoma Missense mutation c.643C>T Endometrium Carcinoma Missense mutation c.7C>T Endometrium Carcinoma Missense mutation c.496A>C Endometrium Carcinoma Missense mutation c.373G>A Endometrium Carcinoma Missense mutation c.346T>C Endometrium Carcinoma Missense mutation c.495A>C Endometrium Carcinoma Missense mutation c.248G>T Kidney Carcinoma Missense mutation c.526G>A Liver Carcinoma Missense mutation c.105C>G Liver Carcinoma Missense mutation c.671C>T Acute Myeloid Leukemia Missense mutation c.695T>G B Cell Acute Lymphoblastic Leukemia   Missense mutation c.2T>A Mantle Cell Lymphoma Missense mutation c.340G>C Marginal Zone Lymphoma Missense mutation c.228C>T Head and Neck Carcinoma Missense mutation c.764G>A Melanoma No sense mutation c.764G>A Melanoma No sense mutation c.755G>A Head and Neck Carcinoma No sense mutation c.755G>A Melanoma No sense mutation c.451C>T Melanoma No sense mutation c.628C>T Pancreas No sense mutation c.137G>A Colon Carcinoma No sense mutation c.620C>G Intestinal Adenocarcinoma No sense mutation c.91C>T Glioblastoma Multiforme No sense mutation c.73G>T Adenocarcinoma No sense mutation c.54G>A Head and Neck Carcinoma No sense mutation c.25G>T Lung Carcinoma No sense mutation Catalogue of Somatic Mutations in Cancer; cBioPortal for Cancer Genomics

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