ALKL1_HUMAN
ID ALKL1_HUMAN Reviewed; 129 AA.
AC Q6UXT8; B7ZMG9;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=ALK and LTK ligand 1 {ECO:0000303|PubMed:34646012, ECO:0000303|PubMed:34819673};
DE AltName: Full=Augmentor beta {ECO:0000303|PubMed:26630010};
DE Short=AUG-beta {ECO:0000303|PubMed:26630010};
DE Flags: Precursor;
GN Name=ALKAL1 {ECO:0000303|PubMed:34646012, ECO:0000303|PubMed:34819673,
GN ECO:0000312|HGNC:HGNC:33775};
GN Synonyms=FAM150A {ECO:0000303|PubMed:26418745};
GN ORFNames=UNQ9433/PRO34745 {ECO:0000303|PubMed:12975309};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=25331893; DOI=10.1073/pnas.1412009111;
RA Zhang H., Pao L.I., Zhou A., Brace A.D., Halenbeck R., Hsu A.W., Bray T.L.,
RA Hestir K., Bosch E., Lee E., Wang G., Liu H., Wong B.R., Kavanaugh W.M.,
RA Williams L.T.;
RT "Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a
RT signaling screen of the extracellular proteome.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:15741-15745(2014).
RN [5]
RP FUNCTION.
RX PubMed=26418745; DOI=10.7554/elife.09811;
RA Guan J., Umapathy G., Yamazaki Y., Wolfstetter G., Mendoza P., Pfeifer K.,
RA Mohammed A., Hugosson F., Zhang H., Hsu A.W., Halenbeck R., Hallberg B.,
RA Palmer R.H.;
RT "FAM150A and FAM150B are activating ligands for anaplastic lymphoma
RT kinase.";
RL Elife 4:E09811-E09811(2015).
RN [6]
RP FUNCTION.
RX PubMed=26630010; DOI=10.1073/pnas.1520099112;
RA Reshetnyak A.V., Murray P.B., Shi X., Mo E.S., Mohanty J., Tome F., Bai H.,
RA Gunel M., Lax I., Schlessinger J.;
RT "Augmentor alpha and beta (FAM150) are ligands of the receptor tyrosine
RT kinases ALK and LTK: Hierarchy and specificity of ligand-receptor
RT interactions.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:15862-15867(2015).
RN [7]
RP STRUCTURE BY ELECTRON MICROSCOPY (1.95 ANGSTROMS) OF 57-129 IN COMPLEX WITH
RP LTK, FUNCTION, DISULFIDE BONDS, AND MUTAGENESIS OF PHE-76; ARG-102 AND
RP ARG-115.
RX PubMed=34646012; DOI=10.1038/s41586-021-03959-5;
RA De Munck S., Provost M., Kurikawa M., Omori I., Mukohyama J., Felix J.,
RA Bloch Y., Abdel-Wahab O., Bazan J.F., Yoshimi A., Savvides S.N.;
RT "Structural basis of cytokine-mediated activation of ALK family
RT receptors.";
RL Nature 600:143-147(2021).
RN [8]
RP STRUCTURE BY NMR OF 60-129, FUNCTION, AND DISULFIDE BONDS.
RX PubMed=34819673; DOI=10.1038/s41586-021-04140-8;
RA Reshetnyak A.V., Rossi P., Myasnikov A.G., Sowaileh M., Mohanty J.,
RA Nourse A., Miller D.J., Lax I., Schlessinger J., Kalodimos C.G.;
RT "Mechanism for the activation of the anaplastic lymphoma kinase receptor.";
RL Nature 600:153-157(2021).
CC -!- FUNCTION: Cytokine that acts as a physiological ligand for receptor
CC tyrosine kinase LTK, leading to its activation (PubMed:25331893,
CC PubMed:26418745, PubMed:26630010, PubMed:34646012, PubMed:34819673).
CC Monomeric ALKAL1 binds to LTK, leading to LTK homodimerization and
CC activation (PubMed:34646012, PubMed:34819673). In contrast to ALKAL2,
CC does not act as a potent physiological ligand for ALK (PubMed:26418745,
CC PubMed:34646012). {ECO:0000269|PubMed:25331893,
CC ECO:0000269|PubMed:26418745, ECO:0000269|PubMed:26630010,
CC ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
CC -!- INTERACTION:
CC Q6UXT8; Q9UM73: ALK; NbExp=7; IntAct=EBI-11691642, EBI-357361;
CC Q6UXT8; P29376: LTK; NbExp=3; IntAct=EBI-11691642, EBI-6596163;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q6UX46}. Cell
CC membrane {ECO:0000305|PubMed:34646012}. Note=Following interaction with
CC receptor tyrosine kinase LTK, associates with the cell membrane,
CC membrane-binding is required to activate LTK.
CC {ECO:0000250|UniProtKB:Q6UX46}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6UXT8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6UXT8-2; Sequence=VSP_055085;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in thyroid and
CC moderate levels in stomach, trachea, small intestine, prostate and
CC brain. {ECO:0000269|PubMed:25331893}.
CC -!- SIMILARITY: Belongs to the ALKAL family. {ECO:0000305}.
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DR EMBL; AY358213; AAQ88580.1; -; mRNA.
DR EMBL; AC013650; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC130641; AAI30642.1; -; mRNA.
DR EMBL; BC130643; AAI30644.1; -; mRNA.
DR EMBL; BC144534; AAI44535.1; -; mRNA.
DR CCDS; CCDS6150.1; -. [Q6UXT8-1]
DR RefSeq; NP_997296.1; NM_207413.3. [Q6UXT8-1]
DR PDB; 7MK7; X-ray; 2.43 A; A/B=60-129.
DR PDB; 7MZZ; NMR; -; A=60-129.
DR PDB; 7NX0; X-ray; 1.95 A; A=57-129.
DR PDBsum; 7MK7; -.
DR PDBsum; 7MZZ; -.
DR PDBsum; 7NX0; -.
DR AlphaFoldDB; Q6UXT8; -.
DR SMR; Q6UXT8; -.
DR BioGRID; 133213; 1.
DR IntAct; Q6UXT8; 2.
DR STRING; 9606.ENSP00000351345; -.
DR iPTMnet; Q6UXT8; -.
DR PhosphoSitePlus; Q6UXT8; -.
DR BioMuta; ALKAL1; -.
DR MassIVE; Q6UXT8; -.
DR PaxDb; Q6UXT8; -.
DR PeptideAtlas; Q6UXT8; -.
DR PRIDE; Q6UXT8; -.
DR Antibodypedia; 24431; 23 antibodies from 8 providers.
DR DNASU; 389658; -.
DR Ensembl; ENST00000358543.9; ENSP00000351345.4; ENSG00000196711.9. [Q6UXT8-1]
DR Ensembl; ENST00000523939.1; ENSP00000430953.1; ENSG00000196711.9. [Q6UXT8-2]
DR GeneID; 389658; -.
DR KEGG; hsa:389658; -.
DR MANE-Select; ENST00000358543.9; ENSP00000351345.4; NM_207413.4; NP_997296.1.
DR UCSC; uc003xrd.4; human. [Q6UXT8-1]
DR CTD; 389658; -.
DR DisGeNET; 389658; -.
DR GeneCards; ALKAL1; -.
DR HGNC; HGNC:33775; ALKAL1.
DR HPA; ENSG00000196711; Tissue enhanced (gallbladder, thyroid gland, urinary bladder).
DR MIM; 619670; gene.
DR neXtProt; NX_Q6UXT8; -.
DR OpenTargets; ENSG00000196711; -.
DR PharmGKB; PA162386433; -.
DR VEuPathDB; HostDB:ENSG00000196711; -.
DR eggNOG; ENOG502RZG1; Eukaryota.
DR GeneTree; ENSGT00940000159969; -.
DR HOGENOM; CLU_126080_0_0_1; -.
DR InParanoid; Q6UXT8; -.
DR OMA; MRAVSEW; -.
DR OrthoDB; 1432187at2759; -.
DR PhylomeDB; Q6UXT8; -.
DR TreeFam; TF333390; -.
DR PathwayCommons; Q6UXT8; -.
DR SignaLink; Q6UXT8; -.
DR BioGRID-ORCS; 389658; 15 hits in 1056 CRISPR screens.
DR GenomeRNAi; 389658; -.
DR Pharos; Q6UXT8; Tbio.
DR PRO; PR:Q6UXT8; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q6UXT8; protein.
DR Bgee; ENSG00000196711; Expressed in gall bladder and 54 other tissues.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005125; F:cytokine activity; IDA:UniProtKB.
DR GO; GO:0030298; F:receptor signaling protein tyrosine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IDA:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:0070378; P:positive regulation of ERK5 cascade; IDA:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProtKB.
DR InterPro; IPR029364; FAM150A/B.
DR PANTHER; PTHR28676; PTHR28676; 1.
DR Pfam; PF15129; FAM150; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cytokine;
KW Disulfide bond; Membrane; Reference proteome; Secreted; Signal.
FT SIGNAL 1..27
FT /evidence="ECO:0000255"
FT CHAIN 28..129
FT /note="ALK and LTK ligand 1"
FT /id="PRO_0000317192"
FT REGION 24..63
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT DISULFID 90..126
FT /evidence="ECO:0000269|PubMed:34646012,
FT ECO:0000269|PubMed:34819673, ECO:0007744|PDB:7MZZ,
FT ECO:0007744|PDB:7NX0"
FT DISULFID 104..113
FT /evidence="ECO:0000269|PubMed:34646012,
FT ECO:0000269|PubMed:34819673, ECO:0007744|PDB:7MZZ,
FT ECO:0007744|PDB:7NX0"
FT VAR_SEQ 110..129
FT /note="YKRCARLLTRLAVSPLCSQT -> IS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_055085"
FT MUTAGEN 76
FT /note="F->E: Slightly reduced affinity for receptor
FT tyrosine kinase LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT MUTAGEN 102
FT /note="R->E: Reduced affinity for receptor tyrosine kinase
FT LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT MUTAGEN 115
FT /note="R->E: Reduced affinity for receptor tyrosine kinase
FT LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT STRAND 64..67
FT /evidence="ECO:0007829|PDB:7MZZ"
FT HELIX 72..81
FT /evidence="ECO:0007829|PDB:7NX0"
FT HELIX 88..90
FT /evidence="ECO:0007829|PDB:7NX0"
FT HELIX 91..99
FT /evidence="ECO:0007829|PDB:7NX0"
FT STRAND 100..102
FT /evidence="ECO:0007829|PDB:7MZZ"
FT HELIX 103..105
FT /evidence="ECO:0007829|PDB:7NX0"
FT HELIX 107..109
FT /evidence="ECO:0007829|PDB:7NX0"
FT HELIX 110..121
FT /evidence="ECO:0007829|PDB:7NX0"
FT HELIX 124..127
FT /evidence="ECO:0007829|PDB:7NX0"
SQ SEQUENCE 129 AA; 14269 MW; 8B4F6D7B5679B4E2 CRC64;
MRPLKPGAPL PALFLLALAL SPHGAHGRPR GRRGARVTDK EPKPLLFLPA AGAGRTPSGS
RSAEIFPRDS NLKDKFIKHF TGPVTFSPEC SKHFHRLYYN TRECSTPAYY KRCARLLTRL
AVSPLCSQT
