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PubMed2006

Activin receptor-like kinases: structure, function and clinical implications.

The transforming growth factor-beta (TGF-beta) superfamily regulates a multitude of cellular processes from fertilization to adulthood in vertebrates. Signaling by the TGF-beta superfamily occurs via formation of heteromeric complexes consisting of type I and type II receptors. The type I receptors, referred to as activin receptor-like kinases (ALK), lie at the epicenter of the signaling cascade as they transduce TGF-beta signals to intracellular regulators of transcription known as Smad proteins. Currently, seven ALKs have been identified in mammals. Structurally, ALKs possess an extracellular binding domain, a transmembrane domain, a GS domain that serves as the site of activation by type II receptors, and a kinase domain that activates downstream signaling molecules. ALKs mediate the effect of TGF-beta superfamily on a variety of cellular processes such as proliferation, differentiation, apoptosis, adhesion and migration, and therefore play important roles in many biological processes. Some ALKs have been implicated in several disorders, including tumorigenesis, hemorrhagic telangiectasia (HHT), immune and renal diseases, and skeletal malfunctions, suggesting that these receptors can be used as drug targets.

Activin Receptors↗
PubMed2000

Isolation and enzyme determination of Candida tropicalis mutants for DCA production.

Techniques, named two-step enrichment and double-time replica-plating method (TEDR), are described that allow a mutated population of Candida tropicalis to be enriched efficiently for mutants deficient in the alkane degradation pathway (Alk(-)) and to be selected easily for mutants increasing in the DCA (dicarboxylic acids) excretion pathway. After C. tropicalis was mutated with ethyl methane sulphonate and ultraviolet, the Alk(-) mutants were enriched (the first step enrichment, up to eightfold in one round of enrichment) by treatment with nystatin in medium SEL1-1. The mutagen-treated cells were then cultured in medium YPD containing chlorpromazine for further enriching (the second-step enrichment, up to threefold in one round) the mutants with an increasing capacity of alpha- and omega-oxidation. On the other hand, the Alk(-) mutants were readily isolated by the SEL1 replica-plating method by using alkane or glucose as the sole carbon source. A total of 43 Alk(-) mutants were isolated from 2x10(8) mutagen-treated cells. In the following steps, by using SEL2 replica plating, the screening studies showed that of the 43 Alk(-) mutants, 11 strains could accumulate DCA greatly from alkane, and strains 1-12 and 1-3, especially, could produce nearly three times as much DCA as the wild-type organism could. The results showed that the strains had more cytochrome P450 activity and a higher converting capacity of alkane.

Journal Article↗
PubMed1998

Genomic DNA amplification and the detection of t(2;5)(p23;q35) in lymphoid neoplasms.

Anaplastic large cell lymphoma (ALCL) is an intermediate grade Non-Hodgkin's lymphoma (NHL) characterized by the frequent presence of the t(2;5)(p23;q35). This translocation fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a protein kinase gene (Anaplastic Lymphoma Kinase, ALK) on chromosome 2p23. In order to determine the frequency of t(2;5) we used a DNA polymerase chain reaction (PCR) amplification using genomic DNA, 5'-primers derived from the NPM gene, and 3'-primers derived from the ALK gene. The presence of amplifiable DNA in the samples was established with PCR and oligonucleotide primers designed to amplify a 3,016 bp fragment from the beta-globin locus. The t(2;5) PCR assay was established using DNA isolated from three t(2;5)-positive ALCL cell lines. Its ability to amplify genomic DNA prepared for routine molecular diagnostic use was validated using archival DNA from four ALCL tumors known to be t(2;5)-positive. Its sensitivity was established by serially diluting t(2;5)-positive DNA in normal DNA: amplicons were generated in 100% of reactions diluted 10(4)-fold (6-8 cells per tube) and in 30% of those diluted 10(5)-fold (0.6-0.8 cells per tube.) We subsequently analyzed archival genomic DNA extracted from 38 ALCL, 77 NHLs, 37 Hodgkin's lymphomas, and 9 lymphomatoid papuloses. The t(2;5) was detected in 6 ALCLs (16%, 95% confidence intervals 6%-31%), but not in any other lymphoma, or in lymphomatoid papulosis. By using the published sequence of the fourth NPM intron that is involved in t(2;5) and by sequencing the individual tumor amplicons and also the normal ALK intron that is involved in t(2;5), we established that all breakpoints involve the same introns in the ALK and NPM loci. Detailed analysis demonstrated that each translocation generates a unique breakpoint sequence, and suggested that sequence homology between the ALK and NPM intron sequences may be involved in the translocation. We conclude that genomic DNA-PCR is useful for the detection of t(2;5) that in our patient population is restricted to ALCL and is not detectable in other NHL, Hodgkin's disease, or lymphomatoid papulosis. More work is needed to determine the prognostic significance of t(2;5), and to establish the utility of the genomic DNA PCR in monitoring minimal residual disease.

Anaplastic Lymphoma Kinase↗
PubMed2001

Primary systemic anaplastic large-cell lymphoma (CD30+): advances in biology and current therapeutic approaches.

In 1985, Stein et al demonstrated the expression of the lymphoid activation antigen CD30/Ki by neoplastic cells. Fifteen years after the first description, anaplastic large-cell lymphomas (ALCL) are now thought to be a heterogeneous group in terms of their clinical, morphologic, phenotypic, cytogenetic, and molecular biology features. However, on the basis of a specific genetic anomaly and expression of a chimeric nucleophosmin anaplastic lymphoma kinase (NPM-ALK) protein and its variants, a distinct clinicopathologic entity defined as "ALK-positive lymphoma" or "ALKoma" can be recognized. Based on molecular and clinical criteria, 3 entities of primary ALCL can be identified: primary systemic ALK positive, primary systemic ALK negative, and primary cutaneous ALCL. This review focuses on advances in the knowledge of primary systemic ALCL biology and discusses therapeutic approaches based on ALK expression. The presence of this protein appears to be an important prognostic factor and, combined with an age-adjusted International Prognostic Index, could allow researchers to design more specific clinical trials aimed at finding new, more efficacious and less toxic treatments.

Age Factors↗
PubMed1976

Antibody responses of mice to alkaline detoxifield lipopolysaccharide.

The antibody responses of outbred normal mice and nude mice injected with alkaline detoxified lipopolysaccharide (Alk-LPS) were measured. In some cases the antibody against lipopolysaccharide (LPS) and native protoplasmic polysaccharide (NPP). The kinetics of the primary responses to Alk-LPS and NPP were similar, whereas LPS stimulated a more rapid appearance of antibodies in the primary responses. Alk-LPS stimulated only primary antibody responses in both types of mice and sensitized nude mice for secondary responses which could be triggered with LPS. However, secondary antibody responses could not be triggered in normal mice primed with Alk-LPS. These data suggested that, on a functional basis, Alk-LPS possessed the specific antigenic signal associated with LPS antigens but lack the second nonspecific mitogenic signal dependent on the lipid A portion of LPS.

Alkalies↗
PubMed2001

Mutation analysis of a family with hereditary hemorrhagic telangiectasia associated with hepatic arteriovenous malformation.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia. Two related genes, endoglin and activin receptor-like kinase (ALK-1), have been mapped to chromosomes 9q34 and 12q13, respectively. We describe a Taiwanese HHT family with hepatic arteriovenous malformation. Clinical and molecular evaluations were performed in eight members of this family, and HHT symptoms were found in three adults. Short tandem repeat markers were used to perform linkage analysis, and this family was classified as HHT type 2 (ALK-1 gene). The exons of ALK-1 were amplified using the polymerase chain reaction and subjected to direct DNA sequencing. The mutation causing the disease was located at ALK-1 codon 411, causing an arginine to glutamine substitution. Five members of this family carried the mutated ALK-1 gene. This investigation successfully used linkage and sequencing techniques to perform molecular diagnosis of HHT.

Activin Receptors, Type I↗
PubMed1992

A novel CoA-independent transacetylase produces the ethanolamine plasmalogen and acyl analogs of platelet-activating factor (PAF) with PAF as the acetate donor in HL-60 cells.

In this study, we demonstrate the presence of a unique membrane-associated transacetylase that transfers the acetate group from platelet-activating factor (PAF) to lysoplasmalogen (in the presence of EDTA and sodium acetate) with the formation of 1-alk-1-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine (alk-1-enylacetyl-GPE). The identity of alk-1-enylacetyl-GPE was confirmed by acid hydrolysis, phospholipases A2 or C treatment and derivatization by fluorodinitrobenzene. The transacetylase has no requirement for Ca2+, Mg2+, or CoA and a broad pH optimum (7.0-8.0) with Km values of 12.0 microM for PAF and 106.4 microM for lysoplasmalogens. The enzyme activity from the isolated membrane fraction is not changed when whole cells are supplemented with 20:4, induced to differentiate into granulocytes, or treated with ionophore A23187. Radyllyso-sn-glycero-3-phosphocholine (GPC), radyllyso-GPE, acyllyso-sn-glycero-3-phosphoserine (GPS), acyllyso-sn-glycero-3-phosphoinositol (GPI), alkyllyso-sn-glycero-3-phosphate (GP), acyllyso-GP, or cis-9-octadecen-1-ol can also serve as acetate acceptors, whereas alkylglycerol, acylglycerol, or cholesterol are inactive. Differences in substrate acceptor specificity, sensitivity toward phenylmethylsulfonyl fluoride, and response to temperature suggest that the CoA-independent transacetylase and the CoA-independent transacylase that transfers long-chain acyl moieties are two separate enzymes. With intact differentiated HL-60 cells, [3H]acetate from [3H]PAF can be incorporated into alk-1-enylacetyl-GPE in the presence of ionophore A23187, but not in its absence. Moreover, phospholipase A2 inhibitors (p-bromophenacyl bromide and mepacrine) block the transacetylation process in whole cell system. These results indicate the production of alk-1-enyllyso-GPE is a rate-limiting factor for the subsequent transacetylation step during cell activation. We conclude that the transacetylase may participate in the biosynthesis of ethanolamine plasmalogen and acyl analogs of PAF, in vivo, fine-tuning of PAF biological responses, and cross-talk between de novo and remodeling pathways of PAF biosynthesis.

Acetates↗
PubMed2003

SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells.

Transforming growth factor-beta (TGF-beta) has growth-stimulating effects on mesenchymal cells and several tumor cell lines. The signaling pathway for this effect is, however, not well understood. We examined how TGF-beta stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-beta, ALK-1 and ALK-5, were expressed and functional in MG63 cells. Of these two receptors, ALK-5 appears to be responsible for the growth stimulation because expression of constitutively active ALK-5, but not ALK-1, stimulated proliferation of MG63 cells. SB-431542 (0.3 microM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-beta-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-beta-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-beta in MG63 cells. Gleevec (1 microM) as well as AG1296 (5 microM) inhibited TGF-beta-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-beta. We also examined the mechanisms of perturbation of growth-suppressing signaling in MG63 cells. We found that expression of c-Myc, which is down-regulated by TGF-beta in many other cells, was up-regulated in MG63 cells, suggesting that up-regulation of c-Myc expression may be the mechanism canceling growth-suppressing signaling of TGF-beta in MG63 cells.

Activin Receptors, Type I↗
PubMed2005

An enzyme-linked immunosorbent assay to screen for inhibitors of the oncogenic anaplastic lymphoma kinase.

The discovery of novel anti-cancer drugs targeting anaplastic lymphoma kinase (ALK), an oncogenic tyrosine kinase, raises the need for in vitro assays suitable for screening compounds for ALK inhibition. To this aim we have developed and optimized an ALK-specific enzyme-linked immunosorbent assay that employs a novel ALK peptide substrate and purified ALK kinase domain.

Amino Acid Sequence↗
PubMedDate not supplied

[Comparison of two lancets in the skin prick test].

BACKGROUND: The skin prick test is used to diagnose the allergic sensitization. Its results depend upon several factors, such as the lancet type. In Cuba, the most frequently used are: ALK lancet and blood lancet. OBJECTIVE: To compare these two lancets regarding the size of the wheal, precision, sensitivity and specificity of the skin prick test and, finally, the preference of the patients to one of them. PATIENTS AND METHODS: The study was performed in 60 allergic patients, aged 15-50 years, seen at the allergy service of Hospital Universitario Clínico Quirúrgico General Calixto García. The skin prick test was performed on the forearm of all patients included, using both lancet types. A negative control (diluent solution) was applied, together with a 54.3 mmol/L histamine solution in five replicates. RESULTS: The mean size of skin reaction to histamine was 6 mm, using a 1 mm single peak lancet (ALK), size was 6.5 mm when using blood lancet (significant difference p < 0.05). Precision, sensitivity and specificity of ALK lancet were 9.7, 100 and 100%, respectively. On the other hand, the respective values for blood lancet were 15.9, 96 and 87%. Of those studied, 27% presented mild pain and 3% moderate pain using the ALK lancet; while 25% showed mild pain and 10% moderate pain using the blood lancet. CONCLUSION: The ALK lancet showed more precision, sensitivity and specificity and it was preferred by the patients.

Adolescent↗
PubMed1985

Lymphocytes from patients with hairy cell leukaemia enable the distinction of two separate subpopulations of activated lymphocyte killer cells generated in mixed lymphocyte culture.

Blood from patients with hairy cell leukaemia (HCL) was used to investigate subpopulations of the non-specific activated lymphocyte killer (ALK) cells generated in mixed lymphocyte culture (MLC). Mononuclear cells from four of five patients with HCL had decreased natural killer (NK) cell activity and, of these, all showed a decrease in ALK cell activity against K-562 target cells (NK like cells), but three had normal levels of ALK cells able to kill melanoma cells. One patient who had received splenectomy had normal NK cell activity, and in MLC his cells generated normal levels of both subpopulations of ALK cells. The results support the hypothesis of separate subsets of ALK cells: NK like cells with NK cell precursors and which preferentially lyse the K-562 target cell and a second separate population which arises independent of NK cell precursors and which has strong cytolytic activity against an NK insensitive melanoma cell line.

Cell Line↗
PubMed1987

Stimulated neutrophils produce an ethanolamine plasmalogen analog of platelet-activating factor.

Human neutrophils stimulated by ionophore A23187 incorporate [3H]acetate into platelet-activating factor and an additional product which is chromatographically similar to phosphatidylethanolamine and accounts for approximately 25% of the [3H]acetate-containing lipids. Three general approaches indicated the sn-1 moiety of the unknown phospholipid is primarily alk-1'-enyl-linked: 1) approximately 80% of the intact phospholipid as well as its derivatives was highly sensitive to hydrolysis by HCl, 2) 80% of the product which resulted from treating the unknown with phospholipase C and acetylating the free hydroxyl group at the sn-3 position, chromatographed with authentic 1-O-alk-1'-enyl-2,3-diacetylglycerol, and 3) catalytic hydrogenation of the diacetylglycerol product described in 2) resulted in a product which chromatographed with alkyldiacetylglycerol and was not sensitive to strong acid. Treatment of the intact phospholipid with phospholipase A2 resulted in the release of 88% of the radiolabel into the acidified aqueous phase of the extraction mixture, indicating the moiety in the sn-2 position remained as acetate and had not been elongated to fatty acid. The head group was determined to be phosphoethanolamine based upon its complete conversion to the dinitro- and trinitrophenyl derivatives by the amine-derivatizing reagents fluorodinitrobenzene and trinitrobenzenesulfonic acid, respectively. From these data is was concluded that the unknown product is 1-O-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine (80%), and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine (10%). Sonicates prepared from neutrophils stimulated with ionophore A23187 contained an acetyltransferase activity capable of utilizing 1-O-alk-1'-enyl-2-lyso-sn-glycero-3-phosphoethanolamine and [14C]acetyl-CoA to produce the product identified as 1-O-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine.

Acetylation↗
PubMed1972

Natural occurrence of free fatty aldehydes in bovine cardiac muscle.

Free fatty acids, aldehydes, alcohols, and 1-O-alkyl and alk-1-enyl glycerols were identified and quantified in lipid extracts from bovine cardiac muscle. Although a number of components present in the free fatty aldehydes were also noted in the fatty chains in the 1-O-alk-1-enyl glycerols, a direct qualitative similarity did not exist as would be expected if the free fatty aldehydes were artifactual in origin. Also, a qualitative similarity did not exist between the fatty chains of the 1-O-alkyl and alk-1-enyl glycerols. This latter observation would suggest a mechanism other than biodehydrogenation of the alkyl ethers for the origin of the alk-1-enyl glycerols. Free fatty aldehydes were distributed evenly between the 105,000 g supernatant and particulate fractions of cardiac muscle, while the 1-O-alk-1-enyl glycerols were associated primarily with the particulate fraction. Free fatty alcohols were noted only in the supernatant fraction, while the 1-O-alkyl glycerols were present in both fractions.

Aldehydes↗
PubMed1984

1-O-alkyl-linked glycerophospholipids of human neutrophils: distribution of arachidonate and other acyl residues in the ether-linked and diacyl species.

This study was done to determine whether human neutrophils contain sufficient 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine to support the synthesis of platelet activating factor by a deacylation-reacylation mechanism, and to examine the relative distribution of arachidonate among the 1,2-diacyl, 1-O-alkyl-2-acyl, and the 1-O-alk-1'-enyl-2-acyl classes of choline- and ethanolamine-containing phospholipids. The predominant phospholipid species of human neutrophils were choline-containing glycerophospholipids (41%), ethanolamine-containing glycerophospholipids (39%), and sphingomyelin (14%), with smaller quantities of phosphatidylserine (4%) and phosphatidylinositol (1%). The choline-linked fraction contained high amounts of 1-O-alkyl-2-acyl-X (44%) and 1,2-diacyl-sn-glycero-3-phosphocholine (47%), and a lesser amount of 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphocholine (9%). In contrast, the ethanolamine-linked fraction contained a large amount of 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine (66%), and lower levels of the 1,2-diacyl (24%) and 1-O-alkyl-2-acyl (10%) species. The major 1-O-alkyl and 1-O-alk-1'-enyl ether chains found in the choline and ethanolamine phospholipid pools were 16:0, 18:0, 18:1, and 20:0. The predominant fatty acyl residues found in the 1,2-diacyl and the sn-2 position of the 1-O-alkyl-2-acyl and 1-O-alk-1'-enyl-2-acyl choline and ethanolamine glycerophospholipids were 16:0, 18:0, 18:1, 18:2, and 20:4.(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed1994

[Pathogenesis and therapy of central serous retinopathy].

UNLABELLED: There is no consensus in the literature on the etiology and therapy of central serous retinopathy. We conducted a retrospective study to find out whether patients treated with argon laser coagulation (ALK) experienced long-term visual acuity improvement. We were also concerned to find whether choroidal perfusion was involved in the etiology. PATIENTS: In all, 28 patients (4 women/24 men) with RCS confirmed by angiography were analyzed. All patients were followed up from 1988 to 1992. Patients with chronic recurrent RCS were not considered. Angiography was performed to examine the type and localization of the leakage and also the choroidal perfusion. Patients who were treated with ALK were compared with patients who were not. RESULTS: Only 9 patients were treated with carefully directed ALK. Their mean visual acuity was 0.5 (STD 0.09) before therapy. After treatment the mean visual acuity was improved to an average of 0.8 (0.23). The follow-up time was up to 56 weeks. The patients without ALK had an initial visual acuity of 0.6 (0.21) which improved to 0.8 (0.22) during an observation period of 60 weeks. By the end of the study the visual acuity was the same in both groups. In 46% of all patients delayed choroidal perfusion was seen on angiography. CONCLUSION: There was no difference in visual acuity between patients treated with and without ALK. The angiographic examinations suggest general changes in choroidal perfusion in patients with RCS.

Adult↗
PubMed1976

Anti-lymphokine antibody. II. Specificity of biological activity.

The present study was designed to explore the range of biologic activity of an anti-lymphokine antiserum (ALKS). This preparation, which was produced by a two-stage immunization procedure, was used to prepare Sepharose bead immunoadsorbent columns. Columns made with ALKS, but not with anti-control antiserum, could specifically remove MIF activity, but not LT, MF, or NCF activity from activated lymphocyte culture supernatants. MIF but not LT, MF, or NCF could be recovered from the beads by acid extraction. These findings, taken in conjunction with the previously described capacity of ALKS to remove MCF and SRF activity from supernatants, demonstrated that ALKS although prepared against a lymphokine preparation with multiple activities, has restricted specificity. Thus far, its traget appear to be those mediators that affect macrophages either in vitro or in vivo. The capacity of ALKS to suppress delayed hypersensitivity reactions in the guinea pig is consistent with these observations, since the macrophage is the predominant infiltrating cell in those reactions.

Animals↗
PubMed1996

Lack of the t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease.

The t(2;5) (p23;q35) chromosomal translocation has been found in a high proportion of lymph node-based CD30+ large cell lymphomas of T-cell lineage. This translocation is believed to result in the expression of a fusion protein containing the catalytic domain of anaplastic lymphoma kinase (ALK) under the control of the promoter for nucleophosmin, a nucleolar phosphoprotein. Expression of ALK activity, which does not normally occur in lymphocytes, is postulated to be involved in the pathogenesis of lymphomas bearing the t(2;5) translocation. Several primary cutaneous lymphoproliferative disorders and Hodgkin's disease are also known to contain CD30+ large lymphoid cells. To determine the role of the t(2;5) translocation in these diseases, we developed a DNA-based polymerase chain reaction (PCR)/Southern blot assay to detect this translocation at the genomic level in lymphomatoid papulosis (14 cases), primary cutaneous CD30+ large cell lymphoma of T-lineage (10 cases) and Hodgkin's disease (13 cases). Two cases of pityriasis lichenoides were also studied. The t(2;5) translocation was not present in any of these specimens. To determine if some other somatic mutation might have resulted in inappropriate expression of ALK catalytic domain, we devised an RNA-based reverse transcriptase-PCR assay to detect transcripts encoded by this ALK region. None were found in the six additional cases of lymphomatoid papulosis that were studied. In aggregate, these results strongly suggest that inappropriate expression of ALK is not involved in the pathogenesis of these CD30+ lymphoproliferative disorders, and that lymph node-based CD30+ large cell lymphoma is a disease that is biologically distinct from skin-based CD30+ lymphoproliferative disorders and Hodgkin's disease. Using methods developed for this report, we also cloned and sequenced the t(2;5) genomic junctional sequences present in the SUP-M2 and SU-DHL-1 cell lines. These intron sequences will be useful for mapping t(2;5) breakpoint clusters.

Adult↗
PubMed1998

Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase is not required for malignant transformation.

The (2;5)(p23;q35) lymphoma-associated chromosomal translocation creates a novel fusion gene that incorporates parts of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and nucleophosmin genes. We report here that the product of this fusion gene accumulates within the nucleoli of neoplastic cells, and that previous reports of a predominantly cytoplasmic localization for the protein represent a tissue-processing artifact. However, nucleolar accumulation of nucleophosmin-ALK may not be necessary for its oncogenic action, because an ALK protein expressed in a lymphoma carrying a variant (1;2) chromosomal translocation did not accumulate in nucleoli. Furthermore, an engineered hybrid TPR-ALK protein can transform rodent fibroblasts and produce lymphomas in mice while remaining confined to the cytoplasm. We propose that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.

Anaplastic Lymphoma Kinase↗