ALKL2_HUMAN
ID ALKL2_HUMAN Reviewed; 152 AA.
AC Q6UX46; B5MC76;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-MAY-2009, sequence version 2.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=ALK and LTK ligand 2 {ECO:0000303|PubMed:30061385};
DE AltName: Full=Augmentor alpha {ECO:0000303|PubMed:26630010, ECO:0000303|PubMed:30061385};
DE Short=AUG-alpha {ECO:0000303|PubMed:26630010, ECO:0000303|PubMed:30061385};
DE Flags: Precursor;
GN Name=ALKAL2 {ECO:0000303|PubMed:30061385, ECO:0000312|HGNC:HGNC:27683};
GN Synonyms=FAM150B {ECO:0000303|PubMed:26418745};
GN ORFNames=UNQ542/PRO1097 {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 2).
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP 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 [4]
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 [5]
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 [6]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, DISULFIDE BONDS, AND SUBCELLULAR
RP LOCATION.
RX PubMed=30061385; DOI=10.1073/pnas.1807881115;
RA Reshetnyak A.V., Mohanty J., Tome F., Puleo D.E., Plotnikov A.N., Ahmed M.,
RA Kaur N., Poliakov A., Cinnaiyan A.M., Lax I., Schlessinger J.;
RT "Identification of a biologically active fragment of ALK and LTK-Ligand 2
RT (augmentor-alpha).";
RL Proc. Natl. Acad. Sci. U.S.A. 115:8340-8345(2018).
RN [7]
RP FUNCTION.
RX PubMed=33411331; DOI=10.15252/embj.2020105784;
RA Borenaes M., Umapathy G., Lai W.Y., Lind D.E., Witek B., Guan J.,
RA Mendoza-Garcia P., Masudi T., Claeys A., Chuang T.P., El Wakil A.,
RA Arefin B., Fransson S., Koster J., Johansson M., Gaarder J.,
RA Van den Eynden J., Hallberg B., Palmer R.H.;
RT "ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of
RT ALK mutation.";
RL EMBO J. 40:e105784-e105784(2021).
RN [8]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.17 ANGSTROMS) OF 78-182 IN COMPLEX WITH
RP ALK, FUNCTION, DISULFIDE BONDS, AND MUTAGENESIS OF PHE-97; HIS-100; ARG-123
RP AND ARG-136.
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 [9]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.27 ANGSTROMS) OF 25-152 IN COMPLEX WITH
RP ALK, STRUCTURE BY NMR OF 77-152, FUNCTION, SUBCELLULAR LOCATION, DISULFIDE
RP BONDS, AND MUTAGENESIS OF CYS-66 AND 94-LYS--HIS-100.
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 kinases LTK and ALK, leading to their activation
CC (PubMed:26418745, PubMed:26630010, PubMed:30061385, PubMed:33411331,
CC PubMed:34646012, PubMed:34819673). Cytokine-binding is sufficient to
CC activate LTK (PubMed:34646012). In contrast, ALKAL2-driven activation
CC of ALK is coupled with heparin-binding to ALK (PubMed:34646012).
CC Stimulation of ALK signaling is involved in neural development and
CC regulation of energy expenditure (PubMed:34646012, PubMed:34819673).
CC {ECO:0000269|PubMed:26418745, ECO:0000269|PubMed:26630010,
CC ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:33411331,
CC ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
CC -!- SUBUNIT: Homodimer; interchain disulfide bond is not required for
CC homodimerization. {ECO:0000269|PubMed:30061385,
CC ECO:0000269|PubMed:34819673}.
CC -!- INTERACTION:
CC Q6UX46; Q9UM73: ALK; NbExp=5; IntAct=EBI-11691780, EBI-357361;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:30061385}. Cell
CC membrane {ECO:0000269|PubMed:34819673}. Note=Following interaction with
CC receptor tyrosine kinase ALK, associates with the cell membrane,
CC membrane-binding is required to activate ALK.
CC {ECO:0000269|PubMed:34819673}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6UX46-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6UX46-2; Sequence=VSP_037017, VSP_037018;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in adrenal
CC gland and modest levels in pancreas, testis and uterus.
CC {ECO:0000269|PubMed:25331893}.
CC -!- SIMILARITY: Belongs to the ALKAL family. {ECO:0000305}.
CC -!- CAUTION: It is unclear whether it activates ALK as a homodimer or a
CC monomer (PubMed:34646012, PubMed:34819673). According to a report,
CC homodimeric ALKAL2 activates ALK (PubMed:34819673). According to a
CC second publication, monomeric ALKAL2 binds and activates ALK
CC (PubMed:34646012). {ECO:0000269|PubMed:34646012,
CC ECO:0000269|PubMed:34819673}.
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DR EMBL; AY358517; AAQ88881.1; -; mRNA.
DR EMBL; AC079779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS46218.1; -. [Q6UX46-1]
DR RefSeq; NP_001002919.2; NM_001002919.2. [Q6UX46-1]
DR RefSeq; XP_005264746.1; XM_005264689.4. [Q6UX46-1]
DR PDB; 7LS0; X-ray; 3.05 A; A/B/C/D=85-152.
DR PDB; 7MZX; NMR; -; A=77-152.
DR PDB; 7N00; EM; 2.27 A; B/D=25-152.
DR PDB; 7NWZ; X-ray; 4.17 A; C/D=78-152.
DR PDBsum; 7LS0; -.
DR PDBsum; 7MZX; -.
DR PDBsum; 7N00; -.
DR PDBsum; 7NWZ; -.
DR AlphaFoldDB; Q6UX46; -.
DR SMR; Q6UX46; -.
DR BioGRID; 129997; 208.
DR IntAct; Q6UX46; 1.
DR STRING; 9606.ENSP00000384604; -.
DR BioMuta; ALKAL2; -.
DR DMDM; 229462850; -.
DR MassIVE; Q6UX46; -.
DR PaxDb; Q6UX46; -.
DR PeptideAtlas; Q6UX46; -.
DR PRIDE; Q6UX46; -.
DR ProteomicsDB; 67564; -. [Q6UX46-1]
DR Antibodypedia; 62864; 2 antibodies from 1 providers.
DR DNASU; 285016; -.
DR Ensembl; ENST00000403610.9; ENSP00000384604.3; ENSG00000189292.16. [Q6UX46-1]
DR Ensembl; ENST00000619265.4; ENSP00000478180.1; ENSG00000189292.16. [Q6UX46-2]
DR GeneID; 285016; -.
DR KEGG; hsa:285016; -.
DR MANE-Select; ENST00000403610.9; ENSP00000384604.3; NM_001002919.3; NP_001002919.2.
DR UCSC; uc002qwi.5; human. [Q6UX46-1]
DR CTD; 285016; -.
DR DisGeNET; 285016; -.
DR GeneCards; ALKAL2; -.
DR HGNC; HGNC:27683; ALKAL2.
DR HPA; ENSG00000189292; Tissue enhanced (adrenal).
DR MIM; 619671; gene.
DR neXtProt; NX_Q6UX46; -.
DR OpenTargets; ENSG00000189292; -.
DR PharmGKB; PA162386448; -.
DR VEuPathDB; HostDB:ENSG00000189292; -.
DR eggNOG; ENOG502S2JY; Eukaryota.
DR GeneTree; ENSGT00940000162505; -.
DR HOGENOM; CLU_187798_0_0_1; -.
DR InParanoid; Q6UX46; -.
DR OMA; SPMCMER; -.
DR OrthoDB; 1432187at2759; -.
DR PhylomeDB; Q6UX46; -.
DR TreeFam; TF333390; -.
DR PathwayCommons; Q6UX46; -.
DR SignaLink; Q6UX46; -.
DR BioGRID-ORCS; 285016; 6 hits in 1057 CRISPR screens.
DR GenomeRNAi; 285016; -.
DR Pharos; Q6UX46; Tbio.
DR PRO; PR:Q6UX46; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q6UX46; protein.
DR Bgee; ENSG00000189292; Expressed in left adrenal gland cortex and 136 other tissues.
DR ExpressionAtlas; Q6UX46; baseline and differential.
DR Genevisible; Q6UX46; HS.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
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 Direct protein sequencing; Disulfide bond; Membrane; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000255, ECO:0000269|PubMed:30061385"
FT CHAIN 25..152
FT /note="ALK and LTK ligand 2"
FT /id="PRO_0000317193"
FT DISULFID 66
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:30061385,
FT ECO:0000269|PubMed:34819673"
FT DISULFID 111..147
FT /evidence="ECO:0000269|PubMed:30061385,
FT ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZX, ECO:0007744|PDB:7NWZ"
FT DISULFID 125..134
FT /evidence="ECO:0000269|PubMed:30061385,
FT ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673,
FT ECO:0007744|PDB:7MZX, ECO:0007744|PDB:7NWZ"
FT VAR_SEQ 17..76
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309"
FT /id="VSP_037017"
FT VAR_SEQ 152
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309"
FT /id="VSP_037018"
FT MUTAGEN 66
FT /note="C->Y: Abolished interchain disulfide bond without
FT affecting homodimerization."
FT /evidence="ECO:0000269|PubMed:34819673"
FT MUTAGEN 94..100
FT /note="KDKFLKH->EDEFLEE: Abolished association with the
FT cell membrane, leading to impaired activation of receptor
FT tyrosine kinase ALK."
FT /evidence="ECO:0000269|PubMed:34819673"
FT MUTAGEN 97
FT /note="F->E: Slightly reduced affinity for receptor
FT tyrosine kinase LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT MUTAGEN 100
FT /note="H->E: Slightly reduced affinity for receptor
FT tyrosine kinase LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT MUTAGEN 123
FT /note="R->E: Reduced affinity for receptor tyrosine kinases
FT ALK and LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT MUTAGEN 136
FT /note="R->E: Reduced affinity for receptor tyrosine kinases
FT ALK and LTK."
FT /evidence="ECO:0000269|PubMed:34646012"
FT STRAND 81..83
FT /evidence="ECO:0007829|PDB:7MZX"
FT HELIX 89..92
FT /evidence="ECO:0007829|PDB:7MZX"
FT HELIX 96..102
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 109..120
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 123..126
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 128..130
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 131..143
FT /evidence="ECO:0007829|PDB:7N00"
FT HELIX 145..148
FT /evidence="ECO:0007829|PDB:7N00"
SQ SEQUENCE 152 AA; 16915 MW; 547047F0FFA23D01 CRC64;
MRGPGHPLLL GLLLVLGAAG RGRGGAEPRE PADGQALLRL VVELVQELRK HHSAEHKGLQ
LLGRDCALGR AEAAGLGPSP EQRVEIVPRD LRMKDKFLKH LTGPLYFSPK CSKHFHRLYH
NTRDCTIPAY YKRCARLLTR LAVSPVCMED KQ
