Gene Section Mini Review

Transcription

1 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review IL22RA1 (interleukin 22 receptor, alpha 1) Pascal Gelebart, Raymond Lai Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada (PG, RL) Published in Atlas Database: February 2010 Online updated version : DOI: /2042/44908 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Other names: CRF2-9, IL22R, IL22R1 HGNC (Hugo): IL22RA1 Location: 1p36.11 DNA/RNA Description The gene spans a region of 23.3 kb including seven exons. Transcription One only transcript form containing 7 exons has been described. The last exon is partially untranslated. The transcript length is 1725 nucleotides, encoding a protein of 594 amino acid residues. Pseudogene None. Protein Description IL22RA1 is composed of 574 amino acid residues, and the predicted molecular weight of the immature protein is 63 kda. IL22RA1 protein is composed of six putative domains, including the signal peptide (residue 1 to 15), the extracellular domain (residue 16 to 228), the transmembrane domain (residue 229 to 249), the cytoplasmic domain (residue 250 to 574), and two fibronectin type-iii domains (residue and ). Representation of the IL22RA1 gene organization. IL22RA1 gene and RNA. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1106

2 IL22RA1 protein organization and localization. IL22RA1 protein domains. Localization of IL22RA1 by immunufluorescence confocal microscopy in ALK+ALCL cells. Expression IL22RA1 expression is relatively restricted, being found at the highest level in the pancreas, small intestine, colon, kidney, and liver. Importantly, IL22RA1 is not detectable in normal immune cells, including monocytes, B-cells, T-cells, natural killer cells, macrophages and dendritic cells, cell types that are normally found in the bone marrow, peripheral blood, thymus and spleen. Localisation IL22RA1 is localized at the plasma membrane. Crystal structure of IL22RA1 with IL22 at 1.9 A resolution. Adapted from PDB (access number: 3DLQ). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1107

3 FACS analysis of IL22RA1 expression in peripheral mononuclear cells from healthy donor. IL22RA1 signaling. Function IL22RA1 is one of the subunits of the IL20, IL22 and IL24 receptor complex. Cytokine binding to IL22RA1 results in its aggregation, which activates the associated JAK via its autophosphorylation. This in turn leads to the phosphorylation and activation of STAT proteins. Subsequently, phosphorylated STAT proteins dimerize and translocate to the nucleus to modulate the transcription of various target genes. Mutations Site-directed mutagenesis experiments have revealed critical amino acid residues involved in its binding to IL22. Specifically, mutation of residue 58 from K to A Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1108

4 reduces the binding of IL22. Mutation of the residue 60 from Y to A or R results in a complete loss of response to IL22. Natural IL22RA1 variants have been reported, including those carrying mutations at the residue 130 (S to P), 205 (V to I), 209 (A to S), 222 (L to P), 407 (M to V) and 518 (R to G). Implicated in ALK-positive anaplastic large cell lymphoma (ALK+ALCL) Disease Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), or ALK+ALCL, is a specific type of non-hodgkin lymphoma characterized by the T/null-cell immunophenotype, consistent expression of CD30 and reciprocal chromosomal translocations involving the ALK gene. In most cases, the chromosomal translocation is that of the t(2;5)(p23;q35), which leads to the juxtaposition of the nucleophosmin (NPM) gene at 5q35 with the ALK gene at 2p23. Mounting evidence suggests that the resulted oncogenic fusion protein, NPM-ALK, plays crucial roles in the pathogenesis of these tumors. Prognosis Patients with ALK+ALCL are typically treated with combination chemotherapy containing doxorubicin. ALK+ALCL represents one of the most common pediatric lymphoid malignancies. The prognosis of pediatric ALK+ALCL patients is significant better than that of adult patients. Cytogenetics t(2;5)(p23;q35) in most ALK+ALCL patients; other translocation variants have been described. Hybrid/Mutated gene NPM-ALK Representation of the NPM-ALK oncoprotein organization and sequence. Abnormal protein NPM-ALK Structure of the oncogenic fusion protein NPM-ALK. Oncogenesis Aberrant expression of IL22RA1 in ALK+ALCL lymphoma cells allows these cells to be responsive to IL-22 stimulation, which further stimulate STAT3 signaling and the growth of these cells. Blocking the IL-22 signaling pathway using a neutralizing antibody has been shown to significantly decrease the growth of ALK+ALCL cells in-vitro. The aberrant expression of IL22RA1 in ALK+ALCL is dependent on the expression of NPM-ALK, since sirna to downregulate NPM-ALK dramatically shut down IL22RA1 expression. References Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem Jan 26;276(4): Lécart S, Morel F, Noraz N, Pène J, Garcia M, Boniface K, Lecron JC, Yssel H. IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functional IL-22 receptor on activated human B cells. Int Immunol Nov;14(11): Wang M, Tan Z, Zhang R, Kotenko SV, Liang P. Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem Mar 1;277(9): Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC. Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. Biochem J Mar 1;370(Pt 2):391-6 Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood Oct 1;110(7): Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1109

5 Bard JD, Gelebart P, Anand M, Amin HM, Lai R. Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma. Leukemia Aug;22(8): Bleicher L, de Moura PR, Watanabe L, Colau D, Dumoutier L, Renauld JC, Polikarpov I. Crystal structure of the IL-22/IL- 22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett Sep 3;582(20): de Oliveira Neto M, Ferreira JR Jr, Colau D, Fischer H, Nascimento AS, Craievich AF, Dumoutier L, Renauld JC, Polikarpov I. Interleukin-22 forms dimers that are recognized by two interleukin-22r1 receptor chains. Biophys J Mar 1;94(5): Dumoutier L, de Meester C, Tavernier J, Renauld JC. New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J Biol Chem Sep 25;284(39): Endam LM, Bossé Y, Filali-Mouhim A, Cormier C, Boisvert P, Boulet LP, Hudson TJ, Desrosiers M. Polymorphisms in the interleukin-22 receptor alpha-1 gene are associated with severe chronic rhinosinusitis. Otolaryngol Head Neck Surg May;140(5):741-7 This article should be referenced as such:. IL22RA1 (interleukin 22 receptor, alpha 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12): Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1110