Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity

Lambert, Que T.; Pradhan, Anuradha; Roll, J. Devon; Reuther, Gary W.

doi:10.1042/bj20110351

Cited by 7 publications

(7 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this observation, IL-27 promoted cell survival of the leukemic cell lines. Our data are in agreement with previous studies (Pradhan and others 2007 , 2010 ; Seita and others 2008 ; Rousseau and others 2010 ; Lambert and others 2011 ). Through functional screening approaches, Pradhan and others ( 2007 , 2010 ) identified IL-27R as a transforming gene from the leukemic cells of a patient with AML and showed that IL-27R is highly expressed on the cell surface of bone marrow cells of AML patients compared with the normal bone marrow cells.…”

Section: Discussionsupporting

confidence: 94%

IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs

Jia

Dilger

Bird

et al. 2016

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

IL-27 is a pleiotropic cytokine of the IL-6/IL-12 family with diverse biological functions. Previous in vivo studies have suggested the antitumor activities of IL-27 in animal models, whereas clinical observations indicate the link of IL-27 in tumor progression. IL-27 has recently been shown to cause inhibition of proliferation on primary leukemic cells from pediatric patients, but information on its role in human leukemic cell lines is limited. In the present study, we investigated the ability of IL-27 to regulate cell growth and survival of various human leukemic cell lines. Our results showed that in human leukemic cell lines coexpressing both IL-27R chains, IL-27Rα and gp130, IL-27 did not inhibit cell growth, but caused dose-dependent proliferation of the acute myeloid leukemic cell line, OCI-AML5, and the erythroleukemic cell lines, TF-1, UT-7, and UT-7/EPO. Consistent with this, IL-27 promoted cell survival and reduced TNF-α-induced apoptosis of the leukemic cell lines. IL-27 also decreased the responsiveness of the leukemic cells to chemotherapeutic drugs, cytarabine and daunorubicin. We observed that IL-27 induced the activation of STAT1/3 and ERK1/2 in the leukemic cells. Growth stimulation by IL-27 was suppressed by the specific MEK inhibitor, U0126, indicating that IL-27-induced cell proliferation is mainly mediated through the activation of the MAPK/ERK signaling pathway. The present study is the first demonstration of the proliferative and antichemotherapeutic properties of IL-27 in human leukemic cell lines, suggesting that IL-27 can play an unfavorable role in tumor growth and can be an important determinant in the chemoresponsiveness of certain subtypes of human leukemia.

show abstract

Section: Discussionsupporting

confidence: 94%

IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs

Jia

Dilger

Bird

et al. 2016

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

show abstract

“…Three cytokine receptors are expressed on EWS: IL17RE, IL27RA, and IL1RAP. A recent mutational study demonstrated that IL27RA has transforming potential, although its expression on non-lymphoid malignancies has not previously been described (Lambert et al, 2011). IL1RAP, Interleukin-1 receptor accessory protein, can exist as a membrane or soluble form and is essential for IL-1 receptor activity.…”

Section: Resultsmentioning

confidence: 99%

Identification of Cell Surface Proteins as Potential Immunotherapy Targets in 12 Pediatric Cancers

Orentas¹,

Yang²,

Wen³

et al. 2012

Front. Oncol.

View full text Add to dashboard Cite

Technological advances now allow us to rapidly produce CARs and other antibody-derived therapeutics targeting cell surface receptors. To maximize the potential of these new technologies, relevant extracellular targets must be identified. The Pediatric Oncology Branch of the NCI curates a freely accessible database of gene expression data for both pediatric cancers and normal tissues, through which we have defined discrete sets of over-expressed transcripts in 12 pediatric cancer subtypes as compared to normal tissues. We coupled gene expression profiles to current annotation databases (i.e., Affymetrix, Gene Ontology, Entrez Gene), in order to categorize transcripts by their sub-cellular location. In this manner we generated a list of potential immune targets expressed on the cell surface, ranked by their difference from normal tissue. Global differences from normal between each of the pediatric tumor types studied varied, indicating that some malignancies expressed transcript sets that were more highly diverged from normal tissues than others. The validity of our approach is seen by our findings for pre-B cell ALL, where targets currently in clinical trials were top-ranked hits (CD19, CD22). For some cancers, reagents already in development could potentially be applied to a new disease class, as exemplified by CD30 expression on sarcomas. Moreover, several potential new targets shared among several pediatric solid tumors are herein identified, such as MCAM (MUC18), metadherin (MTDH), and glypican-2 (GPC2). These targets have been identified at the mRNA level and are yet to be validated at the protein level. The safety of targeting these antigens has yet to be demonstrated and therefore the identified transcripts should be considered preliminary candidates for new CAR and therapeutic antibody targets. Prospective candidate targets will be evaluated by proteomic analysis including Westerns and immunohistochemistry of normal and tumor tissues.

show abstract

“…By unravelling the activation mechanism for these receptors, valuable insights for novel approaches in developing clinically relevant drugs will be gained. The critical nature of the ECD linker and TMDs is highlighted by a number of clinical and experimentally introduced activating mutations for a number of class I cytokine receptors including TPOR (S505N) [ 100 ], IL-27R (F523C) [ 115 ], βc (V449E) [ 113 ], and a number of mutations for EPOR [ 116 ] and GHR [ 44 , 51 ]. These studies expose this vital region as a potential Achilles’ heel for this class of cytokine receptors.…”

Section: Discussionmentioning

confidence: 99%

JAK2 activation by growth hormone and other cytokines

Waters

Brooks

2015

Biochemical Journal

113

View full text Add to dashboard Cite

Growth hormone (GH) and structurally related cytokines regulate a great number of physiological and pathological processes. They do this by coupling their single transmembrane domain (TMD) receptors to cytoplasmic tyrosine kinases, either as homodimers or heterodimers. Recent studies have revealed that many of these receptors exist as constitutive dimers rather than being dimerized as a consequence of ligand binding, which has necessitated a new paradigm for describing their activation process. In the present study, we describe a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations. Binding of the bivalent ligand reorientates and rotates the receptor subunits, resulting in a transition from a form with parallel TMDs to one where the TMDs separate at the point of entry into the cytoplasm. This movement slides the pseudokinase inhibitory domain of one JAK kinase away from the kinase domain of the other JAK within the receptor dimer–JAK complex, allowing the two kinase domains to interact and trans-activate. This results in phosphorylation and activation of STATs and other signalling pathways linked to this receptor which then regulate postnatal growth, metabolism and stem cell activation. We believe that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.

show abstract

Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity

Cited by 7 publications

References 48 publications

IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs

IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs

Identification of Cell Surface Proteins as Potential Immunotherapy Targets in 12 Pediatric Cancers

JAK2 activation by growth hormone and other cytokines

Contact Info

Product

Resources

About