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 02-SEP-2026, entry version 126. 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, GN 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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_001002919.3. [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 PDB; 9G5I; EM; 3.20 A; C=25-152. DR AlphaFoldDB; Q6UX46; -. DR EMDB; EMD-24095; -. DR EMDB; EMD-51087; -. DR SMR; Q6UX46; -. DR BioGRID; 129997; 208. DR FunCoup; Q6UX46; 327. DR IntAct; Q6UX46; 11. DR STRING; 9606.ENSP00000384604; -. DR BioMuta; ALKAL2; -. DR DMDM; 229462850; -. DR MassIVE; Q6UX46; -. DR PaxDb; 9606-ENSP00000384604; -. DR PeptideAtlas; Q6UX46; -. DR ProteomicsDB; 67564; -. [Q6UX46-1] DR Antibodypedia; 62864; 1 antibodies from 1 providers. DR DNASU; 285016; -. DR Ensembl; ENST00000403610.9; ENSP00000384604.3; ENSG00000189292.18. [Q6UX46-1] DR Ensembl; ENST00000896929.1; ENSP00000566988.1; ENSG00000189292.18. [Q6UX46-1] DR Ensembl; ENST00000896934.1; ENSP00000566993.1; ENSG00000189292.18. [Q6UX46-1] DR Ensembl; ENST00000955429.1; ENSP00000625488.1; ENSG00000189292.18. [Q6UX46-1] DR Ensembl; ENST00000955430.1; ENSP00000625489.1; ENSG00000189292.18. [Q6UX46-1] DR Ensembl; ENST00000955431.1; ENSP00000625490.1; ENSG00000189292.18. [Q6UX46-1] 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 AGR; HGNC:27683; -. DR ClinPGx; PA162386448; -. 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 OpenTargets; ENSG00000189292; -. 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; 9807651at2759; -. DR PAN-GO; Q6UX46; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q6UX46; -. DR PathwayCommons; Q6UX46; -. DR Reactome; R-HSA-201556; Signaling by ALK. DR Reactome; R-HSA-9842663; Signaling by LTK. DR SignaLink; Q6UX46; -. DR Agora; ENSG00000189292; -. DR BioGRID-ORCS; 285016; 7 hits in 1135 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 138 other cell types or tissues. DR ExpressionAtlas; Q6UX46; baseline and differential. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; EXP:UniProtKB. 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:0007169; P:cell surface receptor protein tyrosine kinase signaling pathway; IDA:UniProt. 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; ALKL1/2. DR PANTHER; PTHR28676:SF2; ALK AND LTK LIGAND 2; 1. DR PANTHER; PTHR28676; ALK AND LTK LIGAND 2-RELATED; 1. DR Pfam; PF15129; ALKL1_2; 1. DR PDBsum; 7LS0; -. DR PDBsum; 7MZX; -. DR PDBsum; 7N00; -. DR PDBsum; 7NWZ; -. DR PDBsum; 9G5I; -. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cytokine; KW Direct protein sequencing; Disulfide bond; Membrane; KW Proteomics identification; Reference proteome; 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 //