JAK protein tyrosine kinases: their role in cytokine signalling

rewe~,s

55 AL-KHODAIRY,F. and CARR,A. M. (1992) EMBO1. 11, 1343-1350 56 ROWLEY,R., SUBRAMANI,S. and YOUNG, P. G. (1992) EMBO1. 11, 1335-1342 57 ENOCH,T., CARR,A. M. and NURSE,P. (1992) Genes Dev. 6, 2035-2046 58 WEINERT,T. A. (1993) Radiation Res. 132, 141-143 59 ENOCH,T. and NURSE,P. (1990) Cell 60, 665-673 60 ENOCH,T., GOULD, K. L. and NURSE,P. (1991) Cold Spring Harbor Syrup. Quant. BioL 56, 409-416 61 KORNBLUTH,S., SMYI"HE,C. and NEWPORT,J. W. (1992) MoL Cell Biol. 12, 3216-3223 62 FERRELL,I. E, WU, M., GERHART,J. C. and MARTIN,G. S. (1991) MoL Cell BioL 11, 1965-1971

63 800HER, R. N., DESHAIES,R. I. and KIRSCHNER,M. W. (1993) EMBO I. 12, 3417-3426 64 RUSSELL,P., MORENO,S. and REED,S. I. (1989) Ce1157, 295-303 65 SOLOMON,M. I., LEE,T. and KIRSCHNER,M. W. (1992) Mol. Biol. Cell 3, 13-27 66 NASMYIH,K. and HUNT,T. (1993) Nature 366, 634-635 67 HUNTER,T. (1993) Cell 75, 839-841 68 BRIZUELA,L., DRAEI-I'A,G. and BEACH,D. (1987) EMBO1. 6, 3507-3514 69 STUELAND,C. S., LEW,D. J., CISMOWSKI,M. I. and REED,S. I. (1993) MoL Cell Biol. 13, 3744-3755 70 PARGE,H. E., ARVAI,A. S., MURTARI,D. J., REED,S. I. and TAINER,I. A. (1993) Science262, 387-395

Protein tyrosine kinases (PTKs) possess a catalytic domain capable of phosphorylating tyrosine residues on substrate proteins. The importance of this domain for the processing, via cell surface receptors, of extracellular growth-regulatory signals, together with the cacogenic potential of PTKcatalytic domains, underscores the role of tyrosine phosphorylation in the

JAK protein tyrosine kinases: their role in cytokine slgna!,l.-g

regulation of intracellular signal transduction processes. Many extraceilular signals are processed by transmembrane receptors that possess an intracellular PTK domain (Fig. la). Ligand stimulation leads to receptor oligomerization and activation of the kinase

domain, reflected by the phosphorylation of strategically located tyrosine residues in the cytoplasmic portion of the protein. The phosphotyrosines in turn act as recruitment sites for a diverse class of intracellular molecules characterized by the possession of one or more SH2 domainst.a; these domains are able to recognize and bind to phosphorylated tyrosine residues selectively. This highly specific recognition, coupled with the diverse properties of SH2.domain proteins, appears to determine the spectrum of signals transduced in response to a given stimulus. Thus the cellular response to a specific extracellular trigger can be precisely tailored to evoke the appropriate signal transduction pathways by the 'designing' of a receptor complex to include a particular constellation of SH2-domain-binding sites. Cell surface receptors of the cytokine receptor superfamily do not possess intraceilular PTK domains themselves, but many cytokines are known to induce the rapid tyrosine phosphorylation of intracellular proteins, including their own receptors. It has now become clear that these receptors compensate for their lack of an intrinsic PTK activity by recruiting and/or activating intracellular PTKs in response to ligand stimulation (Fig. lb). As is the case for the receptor PTKs, the specificity of signal transduction in response to a given signal may be determined by the constellation of molecules involved in the particular phosphotyrosine-SH2-domain interactions. Recent experiments have revealed that among the known intracellular PTKs recruited by this class of receptor are members of the JAK PTK family. TRENDS IN CELL BIOLOGY VOL. 4 JUNE 1994

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Protein tyrosine kinases (PTKs) are integral components of the cellular machinely that mediates tile transduction and~orprocessing of man), extra, and intracellular signals. Members of the JAK fi,nily of intracellular PTKs (JAKI, JAK2 and TYK2) are chanlcterized by tile possession of a PTK.wlated domain and five additional homology domains, in addition to a classical PTK domain. An important breakthrough ill the understanding of lAK kinase fimction(s) has come fi'om the recent obselvations that many cytokine receptors compensate for their lack of a PTK domain by utilizing members of the JAK family fi~rsignal transduction.

The JAKfamily of PTKs Members of the JAK [an a-ronym of both Janus kinase 0anus, the Roman god of gateways, had two faces) and 'just another kinase'] family of PTKs are characterized by the possession, in addition to a bona fide kinase domain, of a kinase-related domain and five further conserved domains (Fig. 21. in contrast to almost all wholly intracellular PTKs, the members of the JAK family bear no SH2 or SH3 domains. © 1994 ElsevierScienceLid 0962.8924/94/$0700

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(a) Signalling via PTK receptors, Llgand binding induces oligomerizaU~,n of the receptors and activation of their PTK domains. The activated PTKsphosphorylate tyrosine residueson the receptors, which become targets for specific SH2-domaln.containing mediator proteins. (b) Signalling via cytokine receptors lacking PTK domains. Ligand binding induces oligomerization of the receptors, which then recruit and/or activate intracellular PTKs.These PTKsphosphorylate each other and/or the receptors, and the complex becomes a target for a distinct spectrum of SH2.domaln.containing transducer proteins.

"During the last stagesof production of this review,two new IAKfamily membershave been reported: rat JAK3(Ref. 55) and the product of Drosophila

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"l~vomembers of the JAK family were discovered by a modification of the polymerase chain reaction (PCR), using degenerate oligonucleoUde primers based on highly conserved catalytic domain motifs3. cDNAs encoding JAK1 and JAK2 were subsequently characterized 4.s and were demonstrated to share structural homology with a third FTK,TYK2, isolated by low-stringency screening 6,7, To date, these three proteins define the extent of the JAK family of PTKs in mammals, although two other members of this family have been partially characterized following application of a similar PCR-based strategy (Ref. 8; A. G. Harpur and A. F, Wilks, unpublished)'. ]AK1 and ]AK2 are widely expressed in man and mouse,

with JAKI encoded as a single 5.4 kb transcript and JAK2 as two transcripts of 4.8 and 4.4 kb4.s. TY/G?expression (which gives rise to a 4.4 kb transcript) has been observed in a variety of human haematopoietic and turnout cell lines6. The human genes encoding JAK1, JAK2 and TYK2 have been localized to chromosome I (p3!.3) 9,1°,chromosome 9 (p24) 9 and chromosome 19 (p13.2) 6, respectively. JAK1, JAIC?. and TYK2 are proteins of i20-i40kDa and each appears to possess tyrosine kinase activity. In the case of JAK1 and JAK2, this activity seems to be upregulated by various cytokines. This will be discussed in detail below. The structure of the known members of the JAK family is characterized by the presence of seven highly conserved domains VAK homology OH) domainsS; Fig. 2]. The most C-terminal domain OH1) has all the conserved features of a PTK domain (Fig. 3), whose elements have been defined previously by Hanks and Quinn 11. The JH1 domain has been shown to possess tyrosine kinase activity when expressed in bacterial cells as a fusion protein 4. A kinase-related domain 0H2) is located immediately N-terminal to the JH1 domain. This domain has the essence of all the conserved sequence motifs found in the PTK domain, but each of these motifs is more or less subtly modified. Interestingly, these modifications are in turn highly conserved among the JH2 domains of the three JAK family members (Fig. 3). Taken together, these observations question whether the JH2 domain possesses intrinsic klnase activity. Indeed, no kinase activity of the bacterially expressed JH2 domain could be detected for any of a number of exogenous substrates 4. Although the function of the JH2 domain remains unknown at present, the high degree of conservation of the modified residues in the domain suggests that it may have a function that requires the general architecture of a protein ktnase domain. An interesting parallel with the klnase-related domain of the atrial natriuretic peptide receptor guanylate cyclase activity bears examlnatlon. The intrinsic guanylate cyclase activity of the intracellular domain of this p~otein Is regulated by the N-terminal klnase-llke domain In an ATP-dependent manner 12, Although no intrinsic klnase activity has been detected, one explanation might be that the kinas~.like domain is able to regulate the guanylate cyclase activity allosterically, The remaining five domains of homology exhibit varying degrees of conservat|L,n among theJAK family members (Fig. 4). 1he central portion of the JH4 domain and the short JH5 domain are almost perfectly conserved, whereas JH6 and JH7 have only single amino acid conservation or short dispersed stretches of homology. Of potential regulatory importance are the conserved tyrosine residues present within domains JH4 and JH6. The conservation of sequences within protein families has oRen beea an indicator of some structural or functional importance for that particular region, a concept particularly evident for SH2 and PTK catalytic domains. Bearing this in mind, it seems likely that the various JH domains within theJAK family must possess an as yet undefined function(s). TRENDSIN CELLBIOLOGYVOL. 4 JUNE1994

m Involvement of the JAKfamily in cytokine receptor signalling

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The receptors for many members of SH3 domain the cytokine receptor superfamily lack BpklltklTec intrinsic intracellular tyrosine kinase I H domain domains. For example, receptors for the majority, of haematopoietic growth facFes!Fps, Fer [~ JH domain tors, interferons (IFNs), growth hormone (GH), prolactin (PRL) and the ciliary neurotropic factor (CNTF) family Abl, Arg are among this extended group. Most of these receptors are characterized Aok by the presence in the extracellular domains of four positionally conserved Syk, Zap70 cysteine residues and the characteristic sequence motif WSXWS, usually close to a single transmembrane domain ~3. FAK The intracellular domains are remarkably different, with few features JAK1 ,JAK2, held in common. However, two TYK2 elements in the membrane-proximal JH7 JH6 JH5 JH4 JH3 JH2 Jill region are conserved among the family members: a hydrophobic proline-rich FIGURE2 motif close to the transmembrane domain ('box 1'), and an approximately The structural organization of intracellular PTKs.The unique organization of the IAK family 30 amino acid C-terminally located members includes, in addition to a kinase domain (JIll) found in all PTKs,a kinase-related domain acidic motif ('box 2') 14,1s.The integrity (IH2) and five additional conserved IAK homology domains (JH3-7). SH, Src homology; PH, of one or both these domains has pleckstrin homologyS4;]H, IAK homology. been shown to be important for signal Early clues to the likely involvement of the JAK transduction downstream of several cytokine receptors '4,16-t9and they may be involved in recruitment of kinases in cytokine signal transduction came from the observation that purified preparations of GH ancillary molecules necessary for signal processing. receptor contained a receptor-associated phosphoIt has been known for several years that stimulation of many receptors for the cytokine superfamily by tyroslne-containing protein of approximately 120 kDa their respective Iigands triggers a cascade of tyrosine in size37,~8. Similarly, a 130kDa protein phosphorylphosphorylation including that of the receptors ated on tyrosine was found to be closely assoct. themselves 2°,zt. This fact, coupled with th~ obser- ated with the EPO receptor ag. Recent studies have vation that oncogenic forms of several cellular PTKs identified the associated proteins in both cases as abrogate cytoktne dependence ln a numberlof haematopoietic cell lines -2, I XI IIX has suggested that recruitment of PTK ........ G-G--G-V ..................... A-K ................ E ............. activity(s) is a critical event in the CON -L) .... LG-G-FG-VE ..... ---¥DP--D-TGE-VAVK-L ....... H ...... EI-ZL--L-H-NIJtil V-LKVLD--H ...... F-E-AS-M-OVSH-HLpropagation of intracellular signalling a.2 . . . . . . . . . . D - G - - - I e . . . . . . . . . . . . . . . . . . . . . pathways downstream of these recepIV V Via VIb tors. Indeed, several members of the COs . . . . . . . . . . . . . . . . . . . . . . . G-L ......................... GM ............ HRDT, .... KYKG-C---G ..... LIME-LP-GSL--¥L ............ L--A-QIC-GM-YL .... ¥IHRDLA-RN Src family of intracellular PTKs have aal ---GVCV---EN---MV-E-V--GPLD--L .......... W---VA-QL&-AL-¥LE---LVHGNVC-KN been implicated in cytokine-mediated an2 VII VIII signal transduction 18, 23- 25 and a 97kDa ................. K--DFG--K ................. P--W---E ............ SDVW..G putative tyrosine kinase has been cos L V . . . . . . . . . . . . V K I G D F G L K . . . . . . E ¥ ¥ . . . . . . . S P V F W YAPEC .... K..F--ASDVWSFG JH1 PFIKLSDPG ..... L ............. ERIPW-APEC .... K--L--A-DKWSFG reported to be activated by several aa2 - L L cytokines26. A major advance in our IX X XZ understanding of cytokine signalling c o s .... E ....... ...P ............ G ..... . ............. P ............. CW ...... VTL-EL ........ SP--F---IG .... GQM-V-RL---L .... RLP-P--CPDE---LM--CW ...... has come from the recent identlfi- aal -TL-EI .............. C--G--P ........ K--FY .... RLP-P..----L--5---C ....... cation of members of the JAK family aN2 of PTKs as components of signal transduction pathways triggered by aalC°N RR P- -- FF - -.L. . ........ a number of cytokines, including aa2 R P - F R - - - R D IFN-a/I3 and .~/27-29 GHaO, erythropoietin (EPO)31, interleukin 3 (IL-3)n, granulocyte-colony-stimulating factor FIGURE3 (G-CSF)33, PRL34, interleukin 6 (IL- Amino acid comparison of the tyrosine kinase domain (IH1) and the kinase-relateddomain (IH2) ol 6)3s,36, CNTF36, leukaemia inhibitory the JAK family members. The PTK domain consensus sequence (CON) indicates the invariant factor36 (LIF) and oncostatin M amino acids as defined by Hanks and Quinn !1. Dashesindicate nonconserved amino acids, while dots indicate gaps introduced to maximize the alignments. (OSM)36 (Table 1). TRENDS IN CELL BIOLOGYVOL. 4 JUNE 1994

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TABLE 1 - IAK FAMILY MEMBERS IN CVTOKINE SIGNALLING

that binding of IFN to its receptor rapidly induces tyrosine phosphorylation of latent SH2domain-containing cytoplasmic transcription factors (see Ref. 41 Cell arrest, antiviral + ? + 27,28,51 IFN-ot/p for a review). These factors are immune response + + ? 28,29,51 IFN-7 also referred to as STAT proHaematopoietic cell proliferation ? + ? 32 IL-3 teins ('signal transducers and Granulocyte/macrophage differentiation ? + ? 30,31 GM-CSF activators of transcription')4L Induction of eq/thropoiesis ? + ? 31 EPO Treatment with IFN-~/[3 results Proliferation and differentiation of + + ? 33 G-CSF } in tyrosine phosphorylation of various cells, particularly haematopoietic + + +a IL-6 a 113 kDa protein (p113) and and neuronal cells + + ? 36 UF two closely related proteins of Growth inhibition of tumour cells + + ? 36 OSM 91 kDa (p91) and 84 kDa (p84)43, Neuronal cell proliferation and differentiation + + ? 36 CNTF Growth, mammary gland differentiation, ? + ? 30 whereas after IFN-7 treatment GH carbohydrate/lipid metabolism only p91 becomes phosphorylated on tyrosine 44. p91 and p84 PRL Lactogenesis, gonadal cell + + ? 34 function, B/T-cell proliferation are alternatively spliced forms of the same gene; they differ in a aThe involvement of TYK2 varies between cell lines. 38 amino acid extension at the C-terminus of p91 (Ref. 45). Once phosphorylated these proteins JAK2. GH specifically promotes complex formation are translocated to the nucleus where they take part between the receptor and JAK2, leading to phos- in transcriptional activation 4~. phorylation of JAK2 and activation of its inherent Evidence for the direct involvement of members of tyrosine kinase activity3°. Similar ligand-specific the JAK family in IFN-induced signal transduction tyrosine phosphorylation and activation of the JAK2 has come from genetic complementation experkinase have been observed in response to EPO3~ and iments using mutant cell lines defective in various IL-3:4-'.By contrast, activation of both JAK1 and JAK2 components of the IFN signalling pathway. A mutant has been demonstrated in response to PRL:~4,G-CSF:~:~ cell line unresponsive to IFN-ct could be rescued by and members of the CNTF family of cytoktnes transfectlon with genomic DNA encoding the TYK2 (CNTF, I.IF, OSM and IL-6):46.CNTF family members klnase zT. Subsequently, complementatlon expercan also activate TYK2, albeit in a cell-line.dependent iments with cell lines lacktng either a functional JAKI fashion:'. To date, compelling evidence for TYK2 or JAg2 have revealed that all three members of the involvement In cytokine signalling Is limited to the JAK family participate In IFN-tx/I] and -7 signalling IFN-a/13 pathway (see below). both in tertns of p91 tyrostne phosphorylation/ It Is presently unclear what factor(s) determines the activation and a specific transcriptional response ~a,~'. usage of JAK family members. In the case of signalling Interestingly, there appear to be clear delineations by EPO, JAK2 Is a component of a pre.exlsting EPO between the requirements for d|tlerent JAg family receptor complex whose formation is mediated members in the two signalling pathways. While the through the conserved membrane.proximal region :~t. lFN-0t/13 patnCvay requires JAKI and TYK2, the IFN-y The common p receptor components of the CNTF pathway utilizes JAg1 and JAg228,2~. Furthermore, Andrew Ziemiecki family are thought tn form similar complexes with these experiments have also shown that the actiis at the the JAK klnases, with activation requiring ligandvation of either member of a pair [equ|res the other Laboratoryfor induced oligomerization 4o. The interaction between partner In an active form, Indicating that they Clinical and JAK family kinases and the conserved membranecannot be placed In a Jinear pathway zH, Thus the Experimental proximal region of cytokine receptors may well prove initiation of intraceli~lar signal transduction by Research, to be a common theme in cytokine.medlated signal the IFNs requires two active members of the JAK University of transductton, but any proposed mechanism(s) must family. The reciprocal Interdependence between Berne, accommodate several observations. For example, in JAK1 and TYK2 In the IFN-ulI3 pathway and JAK1 Tiefenaustrasse the cell lines examined, EPO and IL-3 stimulated the and JAK2 in the IFN-y pathway may contribute 120, CH-3004 activation of JAK2 alone whereas the CNTF family to the specificity of the cellular response to the Berne, of cytokines, utilizing the common 13 signal-trans. IFNs, for example by influencing the composition Switzerland; and ducing receptor component, activated all the known of multlproteln signalling complexes. To date, the Ailsa Harpur and JAK family memher,~ :~6 Intriguingly, in the case of the complementatlon experiments with IFN signalAndrew Wilks are CNTF family, the JAK family members activated by ling mutants represent the best evidence for diat the Ludwig a single cytokine can vary depending on the cell rect Involvement of the JAK kinases in cytokine Institute for line :~. Clearly, there exist cytokine receptor and cell signalling. Cancer Research, line/type speciflcities that cannot be explained by difMelbourne Tumor ferential expression of JAg family members. Conclusions Biology Branch, It now appears clear that the signal transduction Royal Melbourne IFN signalling via IAK family members pathways initiated by the interaction of many Hospital, Victoria The involvement of tyrosine ,)hosphorylation cytokine receptors with their cognate ligands involve 3050, Australia. in IFN signalling was suggested by the observation members of the JAK family of PTKs. This process Cytokine

Cell/tissue response

Involvement of IAK1 IAK2 TYK2

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TRENDS IN CELL BIOLOGY VOL. 4 JUNE 1994

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J7/7 V I F Y L S D R E P .... L R L G S G E ¥ T F R R L C I R A A Q A C R I S P L C H N L F A L Y D E N T K L W Y A P N R ---//--- V Y L Y N S L S Q A S G S T L N P P S G S T V R E E I C V A A S N A C G I T P V Y N N N P R L M S S T E R I W Y P P N H ---/'/--- ~LHWAGPGGGEP~"v'TFSES S LTAEE~CI H I A H K - G ITPPCF_m~F_AT.~DAOAOVWLPPNH V AEEC IP N RL W N

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echoes themes c o m m o n to signal transT2 duction pathways downstream of PTK growth factor receptors. In each, an 104 137 intracellular kinase domain is activated ;it TITVDDKMSLRLHYRMRFYFTNW---//---LLDASSLEYLFAQGQYDLVKCLAPIRDPKTEQDGHDIE VPH I D S S T A K D I L T A I S P T P P H W - - - / / - - - L L D D F V M S Y L S P Q W R H D F V H G W I K V ...... P V T H E T Q as a consequence of extracellular ligand ;i2 I L E I P R D A S L M L Y F R I R F Y F R N W - - - / / - - -L L D P A S F E Y L F E Q G K H E F V N D V A S L W E L S T E E E I H H F K binding, inducing a cascade of tyrosine T2 W LLD YL Q v H phosphorylation events guided by JH6 SH2-domain interactions. The role of N E C L G N A V L A I S H Y R M M K K M Q L P E L P K D I SYERY I P E T L N K S I R Q R N L L T R M R I N N V F K D F L K E F N N K T ;i1 the conserved JAK family JH domains ;i2 E E C L G N A V L D M M R I A K E K D Q T P L A V Y N S V S Y K T F L P K C V R A K I Q D Y H I L T R K R I R Y R F R R F I Q Q F .... NESLGNAFLHLCHLRLRHGIPLEEVAKKTSFBDCIPRSFRRHIRQHSALTRLRL~FLRDFQ... in the interactions between cytokine T2 E LGNA L A S K P I LTR R F F F receptors and JAK family kinases 272 306 JH5313 349 remains to be elucidated. I C D S S V S T H D L K V K Y L A T L E T L T K H Y G A E - - - / / - - - T G N L G I Q W - - - //---EE. W N N F S F F P E I T H I Recent data have shown that in ;i1 •S Q C K A T A R N L K L K Y L I N L E T L Q S A F Y T E - - - //--- T G N G G I Q W - - - / / - - - E Q D V Q L ¥ C D F P D I I D V ;i2 •. P G R L S Q Q M V M V K Y L A T L E R L A P R F G T E - - - / / - - - T G T G G I Q W - - - / / - - - E P L W A Y F C D F R D I T H V addition to the IFNs 4s,46 and cytoT2 KYL LE L E TG G I Q W E F I kines :¢s,47, growth factors 4s-s2 such as EGF, which activate receptor protein JH4 VIKE ......... SVVS INKQDNKKMELKLS SHEEALSFVSLVDGYFRLTADAHBP/LCTDVAPPLIVHN tyrosine kinases, are also able to elicit ;i1 S IKQANQECSTESRVVTVHKQDGKVLEIELSSLKEALSFVSLIDGYYRLTADAHHYLCKEVAPPAVLEN the tyrosine phosphorylation and ;i2 VLKE ......... HCVS I H R Q D N K C L E L S L P S R A A A L S F V S L V D G Y F R L T A D S S H ~ E V A P P R L V M S T2 K V QD F E L S A L S F V S L DGY R L T A D HYLC VAPP transcriptional activation of the SH2containing p91 and related proteins. 466 493 IQNGCHGPICTEYAINKLRQEGSEEGMYVLRWSCTDFDNILMT---//---GRYSLHGSDRSFPSLGDL Interestingly, stimulation of cells with J1 IHSNCHGPISMDFAISKLKKAGNQTGLYVLRCSPKDFNKYFLT---//---GEYNLSGTKRNFSSLKDL EGF results in the tyrosine phosphorylJ~ I R D G I H G P L L E P F V Q A K L R . . .P E D G L Y L I H W S T S H P Y R L I LT-- - / / - - - G A F V L E G W G R S F P S V R E L T2 I HGP KL G Y S T G L G R F L ation of both p91 and JAK1 sl. These observations illustrate that a Ras-indeJH3 563 pendent 'direct' pathway from the J1 M S H L R K Q I L R T D N I S F M L K R C C Q P K P R E I SNLr'V ....... A T K K A Q E W Q P V Y P M S Q L S F L N C Y Q M E T V R S D S I I F Q F T K C C P P K P K D K S N L L V F R T N G V S D V Q L S P T L G R H N N V N Q M V F membrane receptor to the nucleus may J2 G A A L Q G C L L R A G D D C F S L R R C C L P Q P G E T S N L I I ........ M R G A R A S P R T L N L S Q L S F also be a feature of transmembrane T2 R CC SNL g F receptors with intrinsic PTK activity. It is at present unclear if in all cases a JAK FIGURE 4 kinase(s) is responsible for phosphorylating p91 ~ or If the intrinsic kinase Amino acid comparison of the JAK homology domains JH3-7 of JAK1 (Jl), JAK202) and TYK2 (T2). domain of the growth factor receptor The amino acid numbering corresponds to the JAK1 protein. The deduced consensus sequence is indicated in bold. lq'K can activate p91 s2,s:~. Although stimulation of cells by a References variety of cytokines results in the phosphorylatlon of 1 KOCH,C. A., ANDERSON,D., MORAN,M. F., ELLIS,C. and .IAK family members on tyrosine and induction of PAWSON,T. (1991) Science252, 668-674 autokinase activity, it remains to be formally demon2 MAYER,B. J, and BALTIMORE,D. (1993) Trends Ce//Bio/. 3, 8-13 strated that this reflects an increased activity of JAK 3 WlLKS,A. F, (1989) Proc. Nat/Acad. ~ci. USA 86, 1603-1607 family members as tyrosine klnases in vh,o towards 4 WILKS,A. F., HARPUR,A. G., KURBAN,R. R., RALPH,S. J., substrates such as the receptors themselves or downZUERCHER,G. and ZIEMIECKI,A. (1991) Mo/. Cell Bio/. 11, stream transductlon molecules such as the p91 family. 2057-2065 It is striking that JAKI, JAK2 and TYK2 parth:lpate 5 HARPUR,A. G., ANDRES,A.C., ZIEMIECKI,A., ASTON,R. R. and in many cytoklne signalling pathways that result in WILKS,A. (1992) Oncogene 7, 1347-1353 distinct celkdar responses (Table 1). Clearly, the 6 FIRMBACH-KRAFT,I., BYERS,M., 5HUWS,T., DALLA.FAVERA,R. speclflcRy with respect to signal transduction cannot and KROLEWSKI,J. J. (1990) Oncogene5, 1329-1336 be accounted for by the JAK proteins alone. 7 BERNHARDS,A. (1991) Oncogene6, 1185-1187 Specificity might be economically achieved by use of 8 CANCE,W. G., CRAVEN,R. J., WEINER,T. M. and LIU,E.T. the divergent structure of the cytoplasmic domains (1993) Int./. Cancer.54,571-577 of the various cytokine receptors. One attractive 9 PRITCHARD,M. A., BAKER,E., CALLEN,D. F., SUTHERLAND,G. R. possibility is that after ligand binding and oligomeriand WILKS, A. F. (1992) Mature. Genome3, 36-38 zation, cytokine receptors recruit and/or activate pre10 HOWARD,O. M. Z. et aL (1992) Oncogene7, 895-900 bound.lAK family kinase(s), which phosphorylate the 11 HANKS,S. K. and QUINN,A. M. (1991) Methods Enzymol. 200, receptor and themseiws on tyrosine residues to gen38-62 erate a range of specific SH2-binding sites. These sites 12 CHINKERS,M. and GARBERS,D. L. (1989) Science245, could then attract the appropriate SH2-domain-bear1392-1394 ing transducer molecules (e.g. p91 family members), 13 BAZAN,J. F~(1990) Proc. NatlAcod. Sci. USA 87, 6934-6938 which in turn may become substrates for a second 14 MURAKAMI,M. et al. (1991) Proc. Natl Acad. Sci. USA 88, wave of phosphorylation by the activated JAK 11349-11353 kinases, leading to their biological activation. In this 1S O'NEAL K. D. and YU LEE,L. Y. (1993) Lymphokine C~okine scenario, the JAK family would act as a general 'interRes. 12, 30q-3~2 face' linking ligand-stimulated receptor and target 16 D'ANDREA,A., YOSHIMURA,A., YOUSSOUFIAN,H., ZON, L. t., molecules, and the specificity to the response would KOO, H. W. and LODISH,H. F. (1991) MoL Cell. Biol. 11, be dictated primarily by the structure of the cyto-

plasmic aspect of the cytokine receptor. TRENDS IN CELL BIOLOGY VOL. 4 JUNE 1994

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1 ~ lc

Acknowledgements We thank Anne-Catherine Andresfor stimulating discussionand criticism of the manuscript and Daniel Albrecht for his Corel Draw skills. Work from this laboratory is supported by the Swiss National Science Foundation (31-30015.90), the 8ernese Cancer League and The Foundation for Clinical and Experimental Cancer Resea~ch,

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