ALK_CANLF
ID ALK_CANLF Reviewed; 1631 AA.
AC P0DV84;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 25-MAY-2022, sequence version 1.
DT 03-AUG-2022, entry version 2.
DE RecName: Full=ALK tyrosine kinase receptor {ECO:0000305};
DE EC=2.7.10.1 {ECO:0000250|UniProtKB:Q9UM73};
DE Flags: Precursor;
GN Name=ALK {ECO:0000303|PubMed:25605972};
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Boxer;
RX PubMed=16341006; DOI=10.1038/nature04338;
RA Lindblad-Toh K., Wade C.M., Mikkelsen T.S., Karlsson E.K., Jaffe D.B.,
RA Kamal M., Clamp M., Chang J.L., Kulbokas E.J. III, Zody M.C., Mauceli E.,
RA Xie X., Breen M., Wayne R.K., Ostrander E.A., Ponting C.P., Galibert F.,
RA Smith D.R., deJong P.J., Kirkness E.F., Alvarez P., Biagi T., Brockman W.,
RA Butler J., Chin C.-W., Cook A., Cuff J., Daly M.J., DeCaprio D., Gnerre S.,
RA Grabherr M., Kellis M., Kleber M., Bardeleben C., Goodstadt L., Heger A.,
RA Hitte C., Kim L., Koepfli K.-P., Parker H.G., Pollinger J.P.,
RA Searle S.M.J., Sutter N.B., Thomas R., Webber C., Baldwin J., Abebe A.,
RA Abouelleil A., Aftuck L., Ait-Zahra M., Aldredge T., Allen N., An P.,
RA Anderson S., Antoine C., Arachchi H., Aslam A., Ayotte L., Bachantsang P.,
RA Barry A., Bayul T., Benamara M., Berlin A., Bessette D., Blitshteyn B.,
RA Bloom T., Blye J., Boguslavskiy L., Bonnet C., Boukhgalter B., Brown A.,
RA Cahill P., Calixte N., Camarata J., Cheshatsang Y., Chu J., Citroen M.,
RA Collymore A., Cooke P., Dawoe T., Daza R., Decktor K., DeGray S.,
RA Dhargay N., Dooley K., Dooley K., Dorje P., Dorjee K., Dorris L.,
RA Duffey N., Dupes A., Egbiremolen O., Elong R., Falk J., Farina A., Faro S.,
RA Ferguson D., Ferreira P., Fisher S., FitzGerald M., Foley K., Foley C.,
RA Franke A., Friedrich D., Gage D., Garber M., Gearin G., Giannoukos G.,
RA Goode T., Goyette A., Graham J., Grandbois E., Gyaltsen K., Hafez N.,
RA Hagopian D., Hagos B., Hall J., Healy C., Hegarty R., Honan T., Horn A.,
RA Houde N., Hughes L., Hunnicutt L., Husby M., Jester B., Jones C., Kamat A.,
RA Kanga B., Kells C., Khazanovich D., Kieu A.C., Kisner P., Kumar M.,
RA Lance K., Landers T., Lara M., Lee W., Leger J.-P., Lennon N., Leuper L.,
RA LeVine S., Liu J., Liu X., Lokyitsang Y., Lokyitsang T., Lui A.,
RA Macdonald J., Major J., Marabella R., Maru K., Matthews C., McDonough S.,
RA Mehta T., Meldrim J., Melnikov A., Meneus L., Mihalev A., Mihova T.,
RA Miller K., Mittelman R., Mlenga V., Mulrain L., Munson G., Navidi A.,
RA Naylor J., Nguyen T., Nguyen N., Nguyen C., Nguyen T., Nicol R., Norbu N.,
RA Norbu C., Novod N., Nyima T., Olandt P., O'Neill B., O'Neill K., Osman S.,
RA Oyono L., Patti C., Perrin D., Phunkhang P., Pierre F., Priest M.,
RA Rachupka A., Raghuraman S., Rameau R., Ray V., Raymond C., Rege F.,
RA Rise C., Rogers J., Rogov P., Sahalie J., Settipalli S., Sharpe T.,
RA Shea T., Sheehan M., Sherpa N., Shi J., Shih D., Sloan J., Smith C.,
RA Sparrow T., Stalker J., Stange-Thomann N., Stavropoulos S., Stone C.,
RA Stone S., Sykes S., Tchuinga P., Tenzing P., Tesfaye S., Thoulutsang D.,
RA Thoulutsang Y., Topham K., Topping I., Tsamla T., Vassiliev H.,
RA Venkataraman V., Vo A., Wangchuk T., Wangdi T., Weiand M., Wilkinson J.,
RA Wilson A., Yadav S., Yang S., Yang X., Young G., Yu Q., Zainoun J.,
RA Zembek L., Zimmer A., Lander E.S.;
RT "Genome sequence, comparative analysis and haplotype structure of the
RT domestic dog.";
RL Nature 438:803-819(2005).
RN [2]
RP ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=25605972; DOI=10.1126/scisignal.2005916;
RA Murray P.B., Lax I., Reshetnyak A., Ligon G.F., Lillquist J.S.,
RA Natoli E.J. Jr., Shi X., Folta-Stogniew E., Gunel M., Alvarado D.,
RA Schlessinger J.;
RT "Heparin is an activating ligand of the orphan receptor tyrosine kinase
RT ALK.";
RL Sci. Signal. 8:ra6-ra6(2015).
CC -!- FUNCTION: Neuronal receptor tyrosine kinase that is essentially and
CC transiently expressed in specific regions of the central and peripheral
CC nervous systems and plays an important role in the genesis and
CC differentiation of the nervous system (By similarity). Also acts as a
CC key thinness protein involved in the resistance to weight gain: in
CC hypothalamic neurons, controls energy expenditure acting as a negative
CC regulator of white adipose tissue lipolysis and sympathetic tone to
CC fine-tune energy homeostasis (By similarity). Following activation by
CC ALKAL2 ligand at the cell surface, transduces an extracellular signal
CC into an intracellular response. In contrast, ALKAL1 is not a potent
CC physiological ligand for ALK. Ligand-binding to the extracellular
CC domain induces tyrosine kinase activation, leading to activation of the
CC mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost
CC exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces
CC tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the
CC MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be
CC regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces
CC MAPK pathway activation, which is important for the anti-apoptotic
CC signaling of PTN and regulation of cell proliferation. MDK-binding
CC induces phosphorylation of the ALK target insulin receptor substrate
CC (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-
CC kinase, resulting also in cell proliferation induction. Drives NF-
CC kappa-B activation, probably through IRS1 and the activation of the AKT
CC serine/threonine kinase. Recruitment of IRS1 to activated ALK and the
CC activation of NF-kappa-B are essential for the autocrine growth and
CC survival signaling of MDK (By similarity).
CC {ECO:0000250|UniProtKB:P97793, ECO:0000250|UniProtKB:Q9UM73}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000250|UniProtKB:Q9UM73, ECO:0000255|PROSITE-
CC ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Activated upon ALKAL2 ligand-binding (By
CC similarity). ALKAL2-driven activation is coupled with heparin-binding
CC (PubMed:25605972). Following ligand-binding, homodimerizes and
CC autophosphorylates, activating its kinase activity (By similarity).
CC Inactivated through dephosphorylation by receptor protein tyrosine
CC phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no
CC stimulation by a ligand (By similarity). {ECO:0000250|UniProtKB:Q9UM73,
CC ECO:0000269|PubMed:25605972}.
CC -!- SUBUNIT: Homodimer; homodimerizes following heparin- and ligand-binding
CC (PubMed:25605972). Interacts with CBL, IRS1, PIK3R1 and PLCG1.
CC Interacts with FRS2 and SHC1. Interacts with PTN and MDK (By
CC similarity). {ECO:0000250|UniProtKB:Q9UM73,
CC ECO:0000269|PubMed:25605972}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q9UM73};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:Q9UM73}.
CC Note=Membrane attachment is essential for promotion of neuron-like
CC differentiation and cell proliferation arrest through specific
CC activation of the MAP kinase pathway. {ECO:0000250|UniProtKB:Q9UM73}.
CC -!- DOMAIN: The EGF-like region drives the cytokine specificity for ALKAL2.
CC {ECO:0000250|UniProtKB:Q9UM73}.
CC -!- DOMAIN: The heparin-binding region binds heparin glycosaminoglycan
CC (PubMed:25605972). Heparin-binding is required for ALKAL2-driven
CC activation (By similarity). {ECO:0000250|UniProtKB:Q9UM73,
CC ECO:0000269|PubMed:25605972}.
CC -!- PTM: Phosphorylated at tyrosine residues by autocatalysis, which
CC activates kinase activity. In cells not stimulated by a ligand,
CC receptor protein tyrosine phosphatase beta and zeta complex
CC (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are
CC undergoing autophosphorylation through autoactivation.
CC {ECO:0000250|UniProtKB:Q9UM73}.
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DR EMBL; AAEX03010811; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAEX03010812; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AAEX03010813; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_540136.3; XM_540136.5.
DR STRING; 9615.ENSCAFP00000007913; -.
DR Ensembl; ENSCAFT00845020686; ENSCAFP00845016222; ENSCAFG00845011603.
DR GeneID; 483021; -.
DR eggNOG; KOG1095; Eukaryota.
DR GeneTree; ENSGT00940000159280; -.
DR HOGENOM; CLU_001878_2_2_1; -.
DR TreeFam; TF351636; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR CDD; cd00112; LDLa; 1.
DR CDD; cd06263; MAM; 2.
DR Gene3D; 4.10.400.10; -; 1.
DR InterPro; IPR026830; ALK.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR036055; LDL_receptor-like_sf.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR000998; MAM_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR PANTHER; PTHR24416:SF276; PTHR24416:SF276; 1.
DR Pfam; PF00629; MAM; 2.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00192; LDLa; 1.
DR SMART; SM00137; MAM; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49899; SSF49899; 2.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57424; SSF57424; 1.
DR PROSITE; PS50060; MAM_2; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
PE 3: Inferred from homology;
KW ATP-binding; Cell membrane; Disulfide bond; Glycoprotein; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; Repeat;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..1631
FT /note="ALK tyrosine kinase receptor"
FT /evidence="ECO:0000255"
FT /id="PRO_5023874220"
FT TOPO_DOM 19..1053
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1054..1074
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1075..1631
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 280..443
FT /note="MAM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00128"
FT DOMAIN 494..652
FT /note="MAM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00128"
FT DOMAIN 1131..1407
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 20..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 60..82
FT /note="Heparin-binding region"
FT /evidence="ECO:0000269|PubMed:25605972"
FT REGION 1002..1040
FT /note="EGF-like"
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT REGION 1423..1493
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1526..1554
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1609..1631
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 20..44
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1536..1550
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1264
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1137..1145
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1165
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT CARBOHYD 185
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 260
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 301
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 340
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 427
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 440
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 461
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 579
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 587
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 643
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 724
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 823
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 878
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 879
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 901
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1001
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 703..716
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT DISULFID 798..809
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT DISULFID 921..943
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT DISULFID 1002..1010
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT DISULFID 1005..1021
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
FT DISULFID 1023..1036
FT /evidence="ECO:0000250|UniProtKB:Q9UM73"
SQ SEQUENCE 1631 AA; 176615 MW; FEEB10D03AF57C45 CRC64;
MGSVGLLGLL LLRLSVTASG SGAGTGSGTG SGTGTGTGQL VGSPATGPAL QPREPLSYSR
LQRKSLAVDF VVPSLFRVYA RDLLLPPWSS SEPRAGWTEA RGSLALDCAP LLRLLGPPPG
VSWAEGASSP APAQARTLTR VLKGGSVRKL RRAKQLVLEL GEEAILEGCV GPSPEEVTAG
LLQFNLSELF SWWIRHGEGR LRIRLMPEKK ASAVGREGRL SAAIRASQPR LLFQILGTGH
SSLESPTSLP SPPPDPFAWN LTWIMKDSFP FLSHRSRYGL ECSFDFPCEL EYSPPLHDLG
NQSWSWRRVP SEEASQMDLL DGPETEHSKE MPRGSFLLLN TSANSKHTIL SPWMRSSSEH
CKLAVSVHRH LQPSGRYVAQ LLPHNEPGRE ILLVPTPGKH GWTVLQGRIG RPENPFRVAL
EYISSGNRSL SAVDFFALKN CSEGTSPGSK MALQSSFTCW NGTVLQLGQA CDFHQDCAQG
EDEGQLCSQL PAGFYCNFEN GFCGWSQGIL TPHNPRWQVR TLKDARVQDH RGHALSLSTT
DVPTSESATV TSATFPAPMK NSPCELRMSW LIHGVLRGNV SLVLVENKTG KEQSRMVWHV
ATNEGLSLWQ WTVLPLLDVA DRFWLQIVAW WGQGSRATVA FDNISISLDC YLTISGEEKM
LQNTAPKSRN LFERNPNKDP RPWENTRETP VFDPTVHWLF TTCGASGPHG PTQAQCNNAY
RNSNLSVVVG SEGPLKGIQT WKVPATDTYS ISGYGAAGGK GGKNTMMRSH GVSVLGIFNL
EKGDTLYILV GQQGEDACPS TNRLIQKVCI GENNVIEEEI RVNRSVHEWA GGGGGGGGAT
YVFKMKDGVP VPLIIAAGGG GRAYGAKTDT FHPERLENNS SVLGLNGNSG AAGGGGGWND
NTSLLWSGKS LLEGATGGHS CPQAMKKWGW ETRGGFGGGG GGCSSGGGGG GYIGGNAASN
NDPEMDGEDG VSFISPLGIL YTPALKVMEG HGEVNIKHYL NCSHCEGDEC HMDPESHKVI
CFCDHGTVLA EDGVSCIVSP TPEPHLPLSL VLSVVTSALV AALVLAFSGI MIVYRRKHQE
LQAMQMELQS PEYKLSKLRT STIMTDYNPN YCFAGKTSSI SDLKEVPRKN ITLIRGLGHG
AFGEVYEGQV SGVPSDPSPL QVAVKTLPEV CSEQDELDFL MEALIISKFN HQNIVRCIGV
SLQALPRFIL LELMAGGDLK SFLRETRPRP NQPSSLAMLD LLHVAQDIAC GCQYLEENHF
IHRDIAARNC LLTCPGPGRV AKIGDFGMAR DIYRASYYRK GGCAMLPVKW MPPEAFMEGI
FTSKTDTWSF GVLLWEIFSL GYMPYPSKSN QEVLEFVTSG GRMDPPKNCP GPVYRIMTQC
WQHQPEDRPN FAIILERIEY CTQDPDVINT ALPVEYGPLM EEEEKVPMRP QDPEGIPPLL
VSPPQAKREE GPDPAAPPPL PSTSSGKAAK KPTAAELSGR VTRGPAVEGG HVNMAFSQSN
PASELHKVQG SRNKPTSLWN PTYGSWFTEK PTKKNNPPAT KGHHDRGNLG REGSCTVPPN
VAAGRLPGAS LLLEPSSLTA SMKEVPLFRL RHFPCGNVNY GYQQQGLPFE GTTAPGSSQY
EDALLKTPPG P
