anaplastic lymphoma kinase ( alk ) is a receptor tyrosine kinase of the insulin receptor superfamily , and in mice and humans , the normal expression of alk is largely restricted to the brain and nervous system [ 14 ] .
mice deficient in alk appear to have no overt developmental abnormalities [ 58 ] ; however , behavioural abnormalities have been noted in these mice .
alk - deficient mice perform better on tests of cognitive ability and display less anxiety than their wild - type littermate controls [ 6 , 7 ] .
behavioural tests also demonstrated increased alcohol consumption and altered sensitivity to alcohol in alk - deficient mice compared to wild - type littermates .
intriguingly , single - nucleotide polymorphisms ( snps ) in alk have been identified in humans that correlate with decreased response to alcohol .
a correlation between alk snps and schizophrenia has also been noted in a japanese study . in drosophila melanogaster , the jelly belly protein ( jeb ) has been characterized as an alk ligand [ 1012 ] . in mammals
, there does not appear to be a jeb homologue but two ligands for alk have been described , pleiotrophin   and midkine . however , there is not complete agreement regarding whether these are indeed alk stimulating ligands [ 15 , 16 ] .
more recently , perez - pinera and colleagues proposed an alternative mechanism by which pleiotrophin could be stimulating alk signalling . in their model ,
the binding of pleiotrophin to its known receptor , receptor tyrosine phosphatase / ( rptp / ) , relieves the inhibitory dephosphorylation of alk by rptp / , thereby turning on alk signalling .
dependence receptors induce apoptosis in their nonliganded state , but suppress apoptotic signalling in response to ligand binding .
alk - positive anaplastic large cell lymphomas ( alk+ alcl ) are a distinct subset of non - hodgkin lymphomas with a t or null cell immunophenotype recognized by the world health organization classification scheme for hematological neoplasms [ 58 , 59 ] .
these lymphomas express the cd30 ( ki-1 ) surface antigen , but the morphologic identification of alk+ alcl can be challenging , as the cytologic features of the tumor cells can be highly variable from case to case .
nevertheless , the identification of the so - called  hallmark cells ,  which are characterized by a horseshoe- or kidney - shaped nucleus and a prominent perinuclear golgi body , can facilitate the diagnosis [ 58 , 59 ] . regarding the pathobiology of alk+ alcl
, several groups in the late eighties and early nineties noted that these lymphomas possessed a recurrent chromosomal translocation , the t(2;5)(p23;q35 ) translocation [ 6064 ] . in 1994
, it was demonstrated that this translocation generates a fusion gene between a previously uncharacterized tyrosine kinase on chromosome 2 , and the nucleophosmin ( npm ) gene on chromosome 5 [ 20 , 21 ] .
this kinase was termed alk owing to its association with alcl and the expression of this kinase led to the identification of what is now considered to be a clinically distinct entity , alk+ alcl .
in addition to npm , several other alk translocation partners have since been identified in alk+ alcl [ 23 , 24 , 27 , 2931 , 33 , 39 , 42 , 43 , 45 ] .
these cancers include a portion of inflammatory myofibroblastic tumours ( imt ) [ 25 , 32 , 34 , 43 , 44 , 46 , 55 , 65 ] , nonsmall cell lung carcinomas ( nsclc ) [ 28 , 49 , 54 , 57 ] , diffuse large b - cell lymphomas ( dlbcl ) [ 22 , 3537 , 47 , 48 , 51 ] , colon cancers [ 50 , 56 ] , breast cancers , renal cell carcinomas [ 26 , 52 , 53 ] , and extramedullary plasmacytomas .
two papers also reported detecting tropomyosin 4- ( tpm4-)alk fusion protein expression in some cases of esophageal squamous cell carcinoma [ 40 , 41 ] .
moreover , it has very recently been established that inhibitors of alk are effective at treating patients with alk+ alcl   and other malignancies expressing alk fusion proteins [ 67 , 68 ] .
although not a focus of this paper , alk has been reported to be highly expressed in breast cancer , and alk gene amplifications and activating mutations have been identified in familial and sporadic neuroblastoma [ 7075 ] and thyroid cancer .
the t(2;5)(p23;q35 ) translocation generates a fusion gene termed npm - alk whose transcription is under the control of npm regulatory sites .
npm is a ubiquitously expressed protein that is predominately found in the nucleolus , but can shuttle between the cytoplasm and nucleus .
npm is multifunctional and regulates several cellular activities including transcription , ribosome biogenesis , and the shuttling of proteins between the nucleus and cytoplasm .
the npm - alk fusion gene consists of the first four exons of npm which encodes for the first 117 amino acids of the npm protein , and the alk portion of the fusion includes the exons encoding for the intracellular tail and kinase domain of alk .
importantly , the npm part of the fusion includes the npm dimerization / oligomerization domain [ 80 , 81 ] .
as we will discuss in the next section , this domain is critically important for npm - alk activity , and the presence of a dimerization / oligomerization domain is a common feature of other alk fusion partners .
an essential role for the npm portion of npm - alk was first demonstrated by experiments showing that deletion of the entire npm region of npm - alk generated a protein incapable of transforming nih 3t3 cells .
similarly , bischof et al . demonstrated that npm truncation or deletion mutants were not tyrosine phosphorylated and were unable to transform fischer rat 3t3 cells .
since npm has been reported to form hexamers and other oligomers [ 82 , 83 ] , researchers examined whether npm could be providing an oligomerization domain in npm - alk .
indeed , gel filtration   and sucrose gradient   experiments demonstrated that npm - alk forms oligomeric complexes in an npm - dependent manner .
moreover , npm - alk can dimerize with endogenous npm , and it is believed that this accounts for why some npm - alk is observed in the nucleus .
the basic domain of echinoderm microtubule - associated protein - like 4 ( eml4 ) also functions as a dimerization domain in eml4-alk , and this is likely mediated by a coiled - coil motif within the basic domain .
most other alk fusion partners possess known dimerization / oligomerization domains that are postulated to mediate dimerization / oligomerization of the fusion proteins ( table 2 ) .
msn - alk ( a fusion between moesin and alk ) appears not to have an oligomerization domain and is postulated to be activated through the colocalization of msn - alk fusion proteins to cellular membranes .
thus , dimerization , oligomerization , or colocalization of alk fusion proteins appears to be a common and necessary requirement for these oncoproteins to signal .
npm - alk activates downstream signalling events that promote proliferation , prevent apoptosis , and enhance migration in alk+ alcl ( reviewed in [ 5 , 85 , 86 ] ) .
we will focus on the stat3 , mek / erk , and pi3k / akt pathways , as much is known about the role these pathways play in alk+ alcl pathogenesis .
in particular , we will discuss the cellular processes these pathways regulate in this lymphoma , and how they are regulated by npm - alk signalling .
members of the signal transducer and activator of transcription ( stat ) family of transcription factors are activated by interferon , cytokine , and growth factor receptor signalling .
the tyrosine phosphorylation of stats by tyrosine kinases , particularly the janus kinases ( jaks ) , facilitates the dimerization of stats .
this allows the stats to translocate to the nucleus and promote the transcription of genes involved in proliferation , cell survival , and the immune response [ 87 , 88 ] . in alk+ alcl ,
the activation of stat3 has been strongly implicated in the pathogenesis of this lymphoma ( figure 1 ) .
stat3 is activated in alk+ alcl cell lines and patient samples [ 8991 ] , as well as cells isolated from npm - alk transgenic mice [ 92 , 93 ] , as measured by its phosphorylation on tyrosine 705 .
the inhibition of stat3 in alk+ alcl cell lines , either through the overexpression of a dominant - negative stat3 construct   or decreasing stat3 expression using antisense oligonucleotides , resulted in decreased proliferation and the induction of apoptosis .
stat3 was also required for npm - alk to transform mouse embryo fibroblasts , and for the continued survival of t - cell lymphomas induced in mice by the expression of an npm - alk transgene .
stat3 exerts its biological effects in alk+ alcl through regulating the expression of multiple genes .
microarray studies performed by piva and colleagues demonstrated that knockdown of stat3 altered the expression of ~1500 genes in a variant of the sup - m2 alk+ alcl cell line .
importantly , stat3 functions both as an activator and repressor of transcription , and approximately 60% of the stat3-regulated genes identified by piva et al . were repressed by stat3 .
those genes found to be upregulated by stat3 include : genes that promote proliferation such as cyclin d1 , cyclin d3 , c - myc , icos , c / ebp [ 9397 ] ; those that promote survival such as bcl - xl , survivin , bcl-2 , mcl-1 , bcl2a1 , c / ebp [ 90 , 93 , 97 , 98 ] ; others including cd30 , pd - l1 , timp-1 , socs3 , hif1 , twist1 , il10 , and il2r chain [ 94 , 95 , 99104 ] .
stat3 is also responsible for repressing the expression of t - cell genes that are commonly not expressed in alk+ alcl including cd3 , zap-70 , lat , and slp-76 , and it appears to do so in part through the upregulation of dna methyltransferases ( dnmts ) .
dnmts methylate cpg motifs in promoter regions of genes , and this blocks the binding of some transcription factors and facilitates the recruitment of methyl - c binding proteins to these promoters .
methyl - c binding proteins can then recruit histone deacetylases and methyltransferases that convert promoter regions into transcriptionally inactive heterochromatin .
zhang and colleagues demonstrated that stat3 also promotes the binding of dnmts 13 to the il2r promoter in order to repress il2r gene expression . silencing il2r chain expression appears to be critical in alk+ alcl as re - introduction of the il2r into alk+ alcl cell lines resulted in decreased npm - alk expression and reduced viability .
this study also demonstrated that stat3 enhances dnmt1 expression through the suppression of the dnmt1-targeting microrna , mir-21 .
stat3 is also responsible for the epigenetic silencing of stat5a in alk+ alcl , which prevents stat5a from repressing npm - alk expression and thereby interfering with npm - alk signalling .
given the importance of stat3 transcriptional activity in alk+ alcl , it is not surprising that many mechanisms contribute to the activation of stat3 in this lymphoma .
stat3 [ 89 , 109 ] and jak3   have both been shown to coimmunoprecipitate with npm - alk , and several studies have shown that npm - alk promotes the tyrosine phosphorylation of stat3 [ 89 , 90 , 92 , 93 ] . however , there is not complete agreement regarding whether stat3 tyrosine phosphorylation is jak3 dependent [ 94 , 110 ] , or whether stat3 is tyrosine phosphorylated in a jak3-independent manner , possibly through direct tyrosine phosphorylation by npm - alk .
the serine / threonine phosphatase pp2a has also been implicated in positively regulating stat3 activity in alk+ alcl , as inhibition of pp2a activity with calyculin a was demonstrated to reduce stat3 tyrosine phosphorylation .
stat3 signalling is also likely enhanced in this lymphoma due to the fact that alk+ alcl cell lines do not express the stat3 inhibitor , pias3 . moreover ,
the shp-1 tyrosine phosphatase is often silenced by dna methylation in alk+ alcl [ 112 , 113 ] , and this is likely due in part to the recruitment of dnmts and histone deacetylases to the shp-1 promoter by stat3 . silencing shp-1 in alk+ alcl is important as shp-1 negative regulates npm - alk signalling through either the direct or indirect dephosphorylation of npm - alk , jak2 , and stat3 [ 114116 ] , and the targeting of npm - alk for proteasomal degradation [ 115 , 116 ] .  
cytokine signalling also plays a role in regulating stat3 activity in alk+ alcl . signalling through the il9 , il21 , and il22  
receptors has been shown to promote stat3 activation in this lymphoma , and much of this may be due to autocrine signalling .
furthermore , the expression of the il22r1 subunit of the il22 receptor is promoted by npm - alk , demonstrating a link between npm - alk and cytokine signalling in this lymphoma .
since the il9 and 21 receptors utilize the il2r common  chain , these findings still need to be reconciled with the results of zhang and colleagues which found that the il2r chain is silenced in alk+ alcl .
signalling mediated by the extracellular signal - regulated kinases 1 and 2 ( erk1 and 2 ) promotes proliferation , survival , differentiation , and migration .
these serine / threonine kinases are activated by many growth factor receptors through a well - defined kinase cascade .
this kinase cascade is initiated by the activation of the ras gtpase , which activates the raf-1 serine / threonine kinase .
raf-1 then activates the dual specificity kinases , mapk / erk kinases 1 and 2 ( mek1 and 2 ) , which phosphorylate and activate the erks .
the erk pathway is activated in alk+ alcl cell lines and patient samples [ 122 , 123 ] and plays a central role in promoting cell proliferation and suppressing apoptosis in this cancer ( figure 2 ) .
treatment with the mek1/2 inhibitor , u0126 , was found to reduce proliferation [ 123125 ] and enhance apoptosis [ 124 , 125 ] in alk+ alcl cell lines .
reduced proliferation was also evident when the karpas 299 alk+ alcl cell line was treated with erk1 and/or 2 sirna .
however , only the silencing of erk1 in these cells was found to increase apoptosis .
two important downstream mediators of mek / erk signalling in alk+ alcl are the serine / threonine kinase , mammalian target of rapamycin ( mtor ) , and the junb transcription factor .
the mtor pathway has been demonstrated to be activated in alk+ alcl patient samples , as measured by phosphorylation of mtor [ 125 , 126 ] and downstream targets of mtor signalling [ 123 , 125127 ] .
marzec and colleagues found that treatment of the su - dhl-1 alk+ alcl cell line with mek inhibitors or erk1/2 sirna resulted in reduced phosphorylation of the ribosomal s6 protein ( rps6 ) .
rps6 is a downstream target of mtor signalling , and phosphorylation of rps6 promotes cell growth .
the p70 s6 kinase ( p70s6k ) , which is activated by mtor and phosphorylates rps6 , is also inhibited in su - dhl-1 cells treated with u0126 , but surprisingly not in the sr-786 alk+ alcl cell line .
mek / erk signalling was postulated to activate mtor through inhibition of the tuberous sclerosis complex ( tsc ) .
tsc is a gtpase - activating protein that inhibits mtor through inactivating the rheb gtpase .
the notion that mek / erk signalling inhibits tsc in alk+ alcl is supported by the finding that treatment of su - dhl-1 cells with mek inhibitors resulted in decreased phosphorylation of tsc2 on inhibitory serine 1798 .
the activation of mtor and the phosphorylation of mtor substrates , eukaryotic initiation factor 4e - binding protein-1 ( 4e - bp1 ) and p70s6k , has also been demonstrated to be dependent on pi3k and akt activity in alk+ alcl .
phosphorylation of 4e - bp1 by mtor results in the dissociation of 4e - bp1 from eukaryotic initiation factor 4e ( eif4e ) , which allows eif4e to initiate translation .
however , the importance of the pi3k / akt pathway in the activation of mtor in alk+ alcl has been questioned .
treatment of alk+ alcl cell lines with the mtor inhibitor , rapamycin , resulted in reduced proliferation [ 123 , 125127 , 129 ] and the induction of apoptosis [ 126 , 127 ] .
sirna - mediated knockdown of mtor was similarly found to reduce proliferation and enhance apoptosis in alk+ alcl cell lines . decreased proliferation as a result of mtor inhibition is at least in part due to the dephosphorylation of the retinoblastoma ( rb ) protein , decreased cyclin a expression , and increased expression of the cyclin - dependent kinase inhibitors , p27 and p21 .
increased apoptosis in response to rapamycin treatment is likely due to decreased expression of the antiapoptotic proteins bcl-2 , bcl - xl , mcl-1 , and c - flip
. inhibition of mtor was also demonstrated to reduce the size of npm - alk - expressing murine tumours in immunocompromised mice .
the transcription of junb is also promoted by mek signalling in alk+ alcl cell lines [ 122 , 123 ] , through the ets-1 transcription factor .
interestingly , mtor signalling also contributes to enhanced junb translation in alk+ alcl cell lines through the targeting of junb mrna to ribosome - rich polysomes .
junb is an ap-1 family transcription factor that is highly expressed in alk+ alcl cell lines and patient samples [ 134136 ] and has been shown to promote the proliferation of the karpas 299 alk+ alcl cell line .
junb also influences phenotypic characteristics of this lymphoma through promoting the transcription of cd30 [ 122 , 137 ] and the granzyme b serine protease .
cd30 signalling also activates mek / erk / junb signalling in this lymphoma to further promote cd30 expression .
the activation of raf-1 , mek , and erk in alk+ alcl cell lines is dependent on npm - alk activity [ 124 , 139 ] , and the ectopic expression of npm - alk has also been demonstrated to induce the activation of these proteins [ 123 , 124 , 140 , 141 ] .
npm - alk can activate ras when ectopically expressed in the jurkat t leukemia cell line , and the expression of a dominant negative n17 ras decreased npm - alk - dependent nf - at / ap-1 luciferase activity in jurkat cells .
furthermore , treatment of the su - dhl-1 alk+ alcl cell line with the ras inhibitor , fti-277 , resulted in increased apoptosis and decreased proliferation .
the ras activator , son of sevenless ( sos ) , has been argued to be recruited to npm - alk via the adapter protein grb2 by molecules such as shc , shp2 , and insulin receptor substrate-1 ( irs-1 ) [ 80 , 141143 ] .
ras activation has also been proposed to occur through a plc-dependent activation of ras guanyl nucleotide - releasing protein ( rasgrp ) .
while raf-1 is activated by npm - alk , it does not appear to be required for erk activation in alk+ alcl cell lines .
another map3k , cot / map3k8 , may be the primary activator of mek in this lymphoma .
treatment of the su - dhl-1 cell line with cot sirna or a cot inhibitor decreased erk and mtor activation and reduced cellular proliferation . whether cot is regulated by npm - alk
the phosphatidylinositol 3-kinase ( pi3k)/akt pathway regulates cell growth , differentiation , apoptosis , metabolism , and migration [ 144 , 145 ] .
pi3k is composed of two subunits , a regulatory p85 subunit and a catalytic p110 subunit , and this enzyme phosphorylates inositol phospholipids on the 3 position of the inositol ring [ 144 , 145 ] .
these lipids , in turn , activate a number of pleckstrin homology ( ph ) domain - containing proteins ; most notably the serine / threonine kinase akt [ 144 , 145 ] . signalling through the pi3k pathway promotes cell survival and proliferation in alk+ alcl ( figure 3 ) .
treatment of alk+ alcl cell lines or ba / f3 cells ectopically expressing npm - alk with pi3k inhibitors induces apoptosis and reduces proliferation [ 146 , 147 ] .
pi3k inhibitors also inhibit the transformation of rat-1 fibroblasts by npm - alk , and a dominant negative p85 subunit unable to associate with the p110 subunit was demonstrated to inhibit the ability of npm - alk - expressing ba / f3 cells to form colonies in methylcellulose .
the akt substrate , glycogen synthase kinase-3 ( gsk-3 ) , is an important target of npm - alk signalling in alk+ alcl .
phosphorylation of gsk-3 on serine 9 by akt inhibits gsk-3 activity , and in alk+ alcl this has been argued to be important for preventing gsk-3 from phosphorylating , and targeting for degradation , the antiapoptotic protein mcl-1 and the positive cell cycle - regulator , phosphatase cdc25a .
furthermore , this study showed that phosphorylation of gsk-3 on serine 9 correlated with elevated cdc25a levels in alk+ alcl patient tumour biopsies .
a separate study also demonstrated that npm - alk promotes cdc25a expression through pi3k , through either transcriptional upregulation of cdc25a or enhanced cdc25a mrna stability .
further supporting the notion that inhibition of gsk-3 is an important target of npm - alk signalling , treatment of alk+ alcl cell lines with either gsk-3 shrna or a gsk-3 inhibitor could partially rescue the decreased viability associated with alk inhibitor treatment .
npm - alk / pi3k / akt signalling also activates the sonic hedgehog ( shh ) pathway in alk+ alcl .
shh is a secreted molecule that , when bound to its receptor patched , relieves inhibition of the smoothened co - receptor by patched .
shh and gli1 were found to be highly expressed in primary alk+ alcl patient samples , and their expression in cell lines was dependent on npm - alk and pi3k activity .
it was argued in this study that pi3k - mediated activation of akt is important for inhibiting gsk-3 in order to prevent gsk-3 from phosphorylating gli1 and targeting the protein for proteasomal degradation .
npm - alk was also found to enhance gli1 transcriptional activity , and expression of the gli1 target gene , cyclin d2 .
moreover , the inhibition of gli1 in alk+ alcl cell lines , either through sirna - mediated knockdown or treatment of cells with a smoothened inhibitor , reduced viability and arrested cells in the g1 stage of the cell cycle .
the phosphorylation of foxo3a by akt results in its binding to 14 - 3 - 3 proteins , which sequesters foxo3a in the cytoplasm where it is unable to promote transcription .
foxo3a is phosphorylated in alk+ alcl cell lines and in cells ectopically expressing npm - alk .
accordingly npm - alk signalling results in the down - regulation of the pro - apoptotic protein , bim-1 and the cell cycle - inhibitor , p27 , which are transcriptional targets of foxo3a [ 155 , 156 ] .
npm - alk / pi3k / akt signalling also maintains low levels of p27 by phosphorylating p27 , and thereby targeting p27 for proteasomal degradation [ 157 , 158 ] .
the activation of the pi3k pathway in alk+ alcl is largely dependent on the activity of npm - alk .
pi3k complexes with npm - alk in alk+ alcl cell lines [ 146 , 147 , 159 ] and cells isolated from npm - alk transgenic mice .
the activation of akt in this lymphoma is dependent on npm - alk and pi3k activity [ 126 , 127 , 160 ] , and akt activity is upregulated in a pi3k - dependent manner by ectopically expressed npm - alk in ba / f3 cells [ 127 , 146 , 153 ] .
pten , a lipid phosphatase that dephosphorylates pi3k lipid products [ 144 , 145 ] , is not expressed in some alk+ alcl patient samples , and this may be a contributing factor to akt activation in these patients .
it has been over 15 years since the discovery of the npm - alk oncoprotein . in this time
we have learned much about the signalling pathways activated by npm - alk in alk+ alcl , and how these pathways contribute to proliferation and survival of this lymphoma .
this information has been critical in directing research towards understanding how alk translocations signal and function in other malignancies .
for example , stat3 activation has been observed in clathrin heavy chain- ( ctlc-)alk - expressing dlbcl patient samples , and stat3 , erk , and akt are active in eml4-alk - expressing nsclc cell lines [ 163165 ] ; however , the importance of these pathways in nsclc and their regulation by eml4-alk appears to vary amongst nsclc cell lines [ 163165 ] . yet , even if activation of the stat3 , erk , and pi3k / akt pathways is common to malignancies expressing alk fusion proteins , differences almost certainly exist in the genes regulated by these pathways in the individual cancers
. some of these differences may be important in the pathogenesis of their respective malignancies .
thus , a more thorough characterization of these signalling pathways in other alk fusion protein - expressing malignancies needs to be a priority of future research .
while the information gained from elucidating how npm - alk signals in alk+ alcl has been , and will continue to be , beneficial for understanding how other alk fusion proteins signal , it is clear that these fusion proteins are not identical in their signalling capability . in a study by armstrong and colleagues , nih 3t3 cells expressing the npm- ,
trk - fused gene ( tfg)- , 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase / imp cyclohydrolase ( atic)- , tropomyosin 3 ( tpm3)- , or ctlc - alk fusion proteins at roughly equal levels , differed in their ability to activate stat3 and akt .
the proliferation rate , invasiveness , and ability to form tumours in nude mice also differed amongst the cells expressing the different alk fusion proteins .
similarly , gene expression profiling demonstrated that , while tumours from alk+ alcl patients expressing npm - alk or tpm3-alk shared many commonly regulated genes , distinctly regulated genes were observed .
accordingly , a second focus of future research needs to be a more detailed examination of whether distinctions exist in the signalling pathways or cellular processes regulated by different alk fusion proteins within the same malignancy .
 anaplastic lymphoma kinase ( alk ) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35 ) chromosomal translocation observed in a subset of anaplastic large cell lymphoma ( alcl ) . 
 the npm - alk fusion protein generated by this translocation is a constitutively active tyrosine kinase , and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in alcl . 
 we now know about the existence of nearly 20 distinct alk translocation partners , and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large b - cell lymphomas , nonsmall cell lung carcinomas , and inflammatory myofibroblastic tumours . 
 moreover , the inhibition of alk has been shown to be an effective treatment strategy in some of these malignancies . in this paper 
 we will highlight malignancies where alk translocations have been identified and discuss why alk fusion proteins are constitutively active tyrosine kinases . finally , using alcl as an example 
 , we will examine three key signalling pathways activated by npm - alk that contribute to proliferation and survival in alcl . 
1. The ALK Receptor Tyrosine Kinase
2. The Identification of NPM-ALK and Other ALK Fusion Proteins
3. The Importance of Dimerization/Oligomerization Domains in ALK Fusion Proteins
4. Signalling Pathways Activated by NPM-ALK in ALK+ ALCL
5. The STAT3 Pathway
6. The MEK/ERK Pathway 
7. The PI3K/Akt Pathway
8. Conclusions and Future Perspectives