ISLR

The aliases for ISLR are Meflin, HsT17563, and mesenchymal stromal-cell and fibroblast-expressing Linx paralogue. The gene is part of the I-set family.

The most updated annotation shows the gene spanning from 74,173,710 to 74,176,871 base pairs (3,161 bp) with location on the plus strand at position 15q24.1 (Chromosome 15). The gene contains 3 exons and 4 distinct introns.{{Cite web |title=AceView: Gene:ISLR, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView. |url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=ISLR&submit=Go |url-status=live |archive-url=https://web.archive.org/web/20200923222048/https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=ISLR&submit=Go |archive-date=23 September 2020 |access-date=2 August 2020 |website=www.ncbi.nlm.nih.gov}}

The ISLR gene has two known transcript variants on the plus strand: ISLR transcript variant 1{{Cite journal |date=4 July 2020 |title=Homo sapiens immunoglobulin superfamily containing leucine rich repeat (ISLR), transcript variant 1, mRNA |url=http://www.ncbi.nlm.nih.gov/nuccore/NM_005545.4 |url-status=live |language=en-US |archive-url=https://web.archive.org/web/20200923222111/https://www.ncbi.nlm.nih.gov/nuccore/NM_005545.4 |archive-date=23 September 2020 |access-date=2 August 2020}} and ISLR transcript variant 2.{{Cite journal |date=7 June 2020 |title=Homo sapiens immunoglobulin superfamily containing leucine rich repeat (ISLR), transcript variant 2, mRNA |url=http://www.ncbi.nlm.nih.gov/nuccore/NM_201526.2 |url-status=live |language=en-US |archive-url=https://web.archive.org/web/20200923222123/https://www.ncbi.nlm.nih.gov/nuccore/NM_201526.2 |archive-date=23 September 2020 |access-date=2 August 2020}} Both variants encode for the same protein.{{Cite journal |date=16 February 2019 |title=Homo sapiens immunoglobulin superfamily containing leucine rich repeat (ISLR), transcript variant 2, mRNA |url=http://www.ncbi.nlm.nih.gov/nuccore/NM_201526.1 |url-status=live |language=en-US |archive-url=https://web.archive.org/web/20200923222114/https://www.ncbi.nlm.nih.gov/nuccore/NM_201526.1 |archive-date=23 September 2020 |access-date=2 August 2020}}

Transcript variant 1 is the longer variant with a length of 2,331 bp and contains 2 exons.

Transcript variant 2 is the shorter variant with a length of 2,128 bp and contains 2 exons. This variant differs in the 5' UTR compared to variant 1.

The human gene of ISLR has two alternatively spliced identical isoforms. The domains of the ISLR gene follows as: LRR_8 (leucine-rich repeat), LRR_RI (ribonuclease inhibitor), PCC (polycystin cation channel protein) Super family, and Ig (immunoglobulin).{{Cite web |title=HGNC Symbol Report for ISLR |url=https://www.genenames.org/data/gene-symbol-report/ |url-status=live |archive-url=https://web.archive.org/web/20190924230104/https://www.genenames.org/data/gene-symbol-report/ |archive-date=24 September 2019 |website=genenames.org}}

The predicted isoelectric point of unmodified protein ISLR is 5.3. The calculated molar mass is 46.0 kDa.

The ISLR protein has 428 amino acids (aa) in humans.{{Cite web |title=ISLR [Homo sapiens] - Protein - NCBI |url=https://www.ncbi.nlm.nih.gov/protein/BAA85970.1 |url-status=live |archive-url=https://web.archive.org/web/20200923222117/https://www.ncbi.nlm.nih.gov/protein/BAA85970.1 |archive-date=23 September 2020 |access-date=2 August 2020 |website=www.ncbi.nlm.nih.gov}} Through the Statistical Analysis of Protein Sequences (SAPS) tool, the percentage of most amino acid residues is about its average percentage among human proteins except leucine which shows high abundance compared to a normal protein.{{Cite web |date=27 July 2020 |title=ISLR Protein Analysis SAPS tool |url=https://www.ebi.ac.uk/Tools/seqstats/saps/ |url-status=live |archive-url=https://web.archive.org/web/20200809153053/https://www.ebi.ac.uk/Tools/seqstats/saps/ |archive-date=9 August 2020}} This is expected with the gene containing multiple LRR (leucine-rich repeats) structural motifs. There is a significantly low abundance of methionine (predicted to be 0.5%). In summary, the positively charged amino acid residues overcounts the negatively charged amino acid residues.

File:Phobius Prediction of Signal Peptide and Transmembrane Domain.jpg

Through SAPS tool, there are two predicted identical four-block length repetitive structures that fall within LRR structural motifs: LSHL at 97-100 bp and 172-175 bp.

One high-scoring transmembrane segment was predicted through the SAPS tool from 411 to 428 aa (length 18) with a pocket from 417 to 418 aa. The Phobius prediction for the ISLR protein sequence illustrated the potential transmembrane domain and a signal peptide (Figure 2).{{Cite web |title=Phobius |url=http://phobius.sbc.su.se/ |url-status=live |archive-url=https://web.archive.org/web/20190427040943/http://phobius.sbc.su.se/ |archive-date=27 April 2019}} The SignalP-5.0 prediction for the signal peptide reported a likelihood of 0.9989 with a cleavage site between position 18 and 19 with the probability of 0.9146.{{Cite web |title=SignalP-5.0 |url=http://www.cbs.dtu.dk/services/SignalP/ |url-status=live |archive-url=https://web.archive.org/web/20200731073102/http://www.cbs.dtu.dk/services/SignalP/ |archive-date=31 July 2020}}

Phosphorylation Sites

There are 31 predicted phosphorylation sites in the protein sequence for ISLR in humans from NetPhos.{{Cite web |date=27 July 2020 |title=NetPhos Prediction for BAA85970.1_ISLR (Homo sapiens) |url=http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5F2693810000546375ED2C95&wait=20 |url-status=live |archive-url=https://web.archive.org/web/20200923222124/http://www.cbs.dtu.dk/cgi-bin/webface2.fcgi?jobid=5F2693810000546375ED2C95&wait=20 |archive-date=23 September 2020}} The results were filtered for best predictions for each residue display and accounted for serine, threonine, and tyrosine.

Through Eukaryotic Structural Motif (ELM tool) predictions, eight distinct phosphorylation sites were identified for the protein:{{Cite web |title=Eukaryotic Linear Motif (ELM) resource for Functional Sites in Proteins (BAA85970.1 ISLR_Human) |url=http://elm.eu.org/cgimodel.py?fun=smartResult&userId=QiKRm5mcu3&EXPECT_CUTOFF=100&r=1&bg=on }}

1. Glycogen synthase kinase-3 (GSK3){{Cite web |title=ELM - Detail for MOD_GSK3_1 |url=http://elm.eu.org/elms/MOD_GSK3_1.html |url-status=live |archive-url=https://web.archive.org/web/20200129130108/http://elm.eu.org/elms/MOD_GSK3_1.html |archive-date=29 January 2020 |access-date=2 August 2020 |website=elm.eu.org}} phosphorylation site at position 234-241 aa.
2. Phosphatidylinositol 3-kinase related kinase (PIKK) phosphorylation site{{Cite web |title=ELM - Detail for MOD_PIKK_1 |url=http://elm.eu.org/elms/MOD_PIKK_1.html |url-status=live |archive-url=https://web.archive.org/web/20200220220408/http://elm.eu.org/elms/MOD_PIKK_1.html |archive-date=20 February 2020 |access-date=2 August 2020 |website=elm.eu.org}} at position 238-244 aa.
3. Casein kinase (CK1) phosphorylation site{{Cite web |title=ELM - Detail for MOD_CK1_1 |url=http://elm.eu.org/elms/MOD_CK1_1.html |url-status=live |archive-url=https://web.archive.org/web/20200830032246/http://elm.eu.org/elms/MOD_CK1_1.html |archive-date=30 August 2020 |access-date=2 August 2020 |website=elm.eu.org}} at position 335-341 aa.
4. Two CK2 phosphorylation sites{{Cite web |title=ELM - Detail for MOD_CK2_1 |url=http://elm.eu.org/elms/MOD_CK2_1.html |url-status=live |archive-url=https://web.archive.org/web/20200915154606/http://elm.eu.org/elms/MOD_CK2_1.html |archive-date=15 September 2020 |access-date=2 August 2020 |website=elm.eu.org}} at positions 343-349 aa and 376-382 aa.
5. Proline-Directed (MAPK) phosphorylation site{{Cite web |title=ELM - Detail for MOD_ProDKin_1 |url=http://elm.eu.org/elms/MOD_ProDKin_1.html |url-status=live |archive-url=https://web.archive.org/web/20200129125637/http://elm.eu.org/elms/MOD_ProDKin_1.html |archive-date=29 January 2020 |access-date=2 August 2020 |website=elm.eu.org}} at position 343-349 aa.
6. Polo-like kinase phosphosites 1 (Plk1) at positions 336-342 aa and 351-357 aa. Ser/Thr residues are phosphorylated by the kinase.{{Cite web |title=ELM - Detail for MOD_Plk_1 |url=http://elm.eu.org/elms/MOD_Plk_1.html |url-status=live |archive-url=https://web.archive.org/web/20200220221104/http://elm.eu.org/elms/MOD_Plk_1.html |archive-date=20 February 2020 |access-date=2 August 2020 |website=elm.eu.org}}
7. Plk4 phosphosite at position 415-421 aa. Ser/Thr residues are phosphorylated by the kinase.{{Cite web |title=ELM - Detail for MOD_Plk_4 |url=http://elm.eu.org/elms/MOD_Plk_4.html |url-status=live |archive-url=https://web.archive.org/web/20200220220718/http://elm.eu.org/elms/MOD_Plk_4.html |archive-date=20 February 2020 |access-date=2 August 2020 |website=elm.eu.org}}
8. Two NEK2 phosphorylation sites{{Cite web |title=ELM - Detail for MOD_NEK2_1 |url=http://elm.eu.org/elms/MOD_NEK2_1.html |url-status=live |archive-url=https://web.archive.org/web/20200220220050/http://elm.eu.org/elms/MOD_NEK2_1.html |archive-date=20 February 2020 |access-date=2 August 2020 |website=elm.eu.org}} at positions 415-420 bp and 423-428 aa.

Table 1. Results of ELM motif search after context, structural, and globular domain filtering with acceptable structural score (above medium threshold score). There are 23 total identified post-translational modifications including phosphorylation sites in the human protein of ISLR.

Glycosylation Sites

Through the Simple Modular Architecture Research (SMART) tool{{Cite web |title=SMART: Main page |url=http://smart.embl-heidelberg.de/ |url-status=live |archive-url=https://web.archive.org/web/20200727041338/http://smart.embl-heidelberg.de/ |archive-date=27 July 2020 |access-date=2 August 2020 |website=smart.embl-heidelberg.de |language=en}} in Figure 3, an annotation predicted three N-linked glycosylation sites (red circles, starting from the left): 51 aa, 60 aa, and 309 aa. The LRR structural motifs and immunoglobulin C-2 type (IGc2) domain are shown in the diagram (Figure 3).

File:Predicted N-linked Glycosylation sites in SMART for human ISLR protein..jpg

Amidation Sites

Predicted with MyHits which investigates relationships between protein sequences and motifs,{{Cite web |title=MyHits |url=https://myhits.sib.swiss/ |url-status=live |archive-url=https://web.archive.org/web/20200923222122/https://myhits.sib.swiss/ |archive-date=23 September 2020 |access-date=2 August 2020 |website=myhits.sib.swiss |language=en}} an amidation site motif was confidently predicted at position 355-358 aa.

Palmitoylation sites

Three palmitoylation sites were predicted (Table 2).

Table 2. Results of the CSS-Palm{{Cite web |title=CSS-Palm - Palmitoylation Site Prediction |url=http://csspalm.biocuckoo.org/ |url-status=dead |archive-url=https://web.archive.org/web/20090215130857/http://csspalm.biocuckoo.org/ |archive-date=15 February 2009 |access-date=2 August 2020 |website=csspalm.biocuckoo.org}} for the human protein of ISLR.

GPI-Modifications

Predicted with big-PI predictor,{{Cite web |title=GPI Modification Site Prediction |url=http://mendel.imp.ac.at/sat/gpi/gpi_server.html |url-status=dead |archive-url=https://web.archive.org/web/20200721214740/http://mendel.imp.ac.at/sat/gpi/gpi_server.html |archive-date=21 July 2020 |access-date=2 August 2020 |website=mendel.imp.ac.at}} one glucose phosphate isomerase (GPI) modification was found at position 401 aa (best site) with P-value score of 1.71e-03.{{Cite web |title=big-PI Predictor of BAA85970.1_ISLR (Homo sapiens) |url=http://mendel.imp.ac.at/gpi/cgi-bin/gpi_pred.cgi |url-status=live |archive-url=https://web.archive.org/web/20180220195436/http://mendel.imp.ac.at/gpi/cgi-bin/gpi_pred.cgi |archive-date=20 February 2018}}

Of all the predicted beta sheets, four stretches at 253-260 aa, 265-272 aa, 323-331 aa, and 335-346 aa were identified with high confidence using CFSSP{{Cite web |title=CFSSP: Chou & Fasman Secondary Structure Prediction Server |url=http://www.biogem.org/tool/chou-fasman/index.php |url-status=live |archive-url=https://web.archive.org/web/20200809165036/http://www.biogem.org/tool/chou-fasman/index.php |archive-date=9 August 2020 |access-date=2 August 2020 |website=www.biogem.org}} and Phyre2.{{Cite web |title=PHYRE2 Protein Fold Recognition Server |url=http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |url-status=live |archive-url=https://web.archive.org/web/20200811172958/http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index |archive-date=11 August 2020 |access-date=2 August 2020 |website=www.sbg.bio.ic.ac.uk}} Of all the predicted alpha helices, three alpha helices at 5-15 aa, 189-195 aa, and 214-216 aa were identified with high confidence as well. A tertiary model of the human ISLR protein predicted by I-TASSER{{Cite web |title=I-TASSER server for protein structure and function prediction |url=https://zhanglab.ccmb.med.umich.edu/I-TASSER/ |url-status=live |archive-url=https://web.archive.org/web/20200730105213/https://zhanglab.ccmb.med.umich.edu/I-TASSER/ |archive-date=30 July 2020 |access-date=2 August 2020 |website=zhanglab.ccmb.med.umich.edu}} shows a combination of some alpha helices and beta sheets (Figure 1). Based on the secondary structure prediction of the protein in I-TASSER, the locations of the four beta sheets and three alpha helices confirms the predictions of high confidence made by CFSSP and Phyre2.

The ISLR protein in humans is expected to localize throughout a cell, including extracellular region, based on the predicted results of PSORT II.{{Cite web |title=PSORT: Protein Subcellular Localization Prediction Tool |url=https://www.genscript.com/psort.html |url-status=live |archive-url=https://web.archive.org/web/20200611042016/https://www.genscript.com/psort.html |archive-date=11 June 2020 |access-date=2 August 2020 |website=www.genscript.com}} The Reinhardt's method for cytoplasmic/nuclear discrimination predicted the protein to be more cytoplasmic with a reliability of 76.7. Additionally, ISLR was shown to localize in the cytoplasm based on the polyclonal antibody results in immunohistochemically stained human tissues in myocytes, glandular cells, skin, hepatocytes. Immunofluorescent staining of ISLR in human cell line BJ (fibroblasts) showed localization to the plasma membrane using ISLR Polyclonal Antibody as well.{{Citation |title=Polyclonal Antibody |date=7 February 2020 |work=Definitions |publisher=Qeios |doi=10.32388/lwiy89 |doi-access=free }}

In humans, RNA-seq was conducted on tissue samples from 95 individuals representing 27 different tissues to determine tissue-specificity of all protein-coding genes.{{cite journal | vauthors = Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M | display-authors = 6 | title = Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 2 | pages = 397–406 | date = February 2014 | pmid = 24309898 | pmc = 3916642 | doi = 10.1074/mcp.M113.035600 | doi-access = free }} Notably, there is high expression of ISLR in endometrium and ovary and visible expression among 25 other tissues. Another study of RNA Sequencing of total RNA from 20 human tissues demonstrated high expression of ISLR in uterus.{{cite journal | vauthors = Duff MO, Olson S, Wei X, Garrett SC, Osman A, Bolisetty M, Plocik A, Celniker SE, Graveley BR | display-authors = 6 | title = Genome-wide identification of zero nucleotide recursive splicing in Drosophila | journal = Nature | volume = 521 | issue = 7552 | pages = 376–9 | date = May 2015 | pmid = 25970244 | pmc = 4529404 | doi = 10.1038/nature14475 | bibcode = 2015Natur.521..376D }} Tissue-specific circular RNA induction during human fetal development showed steady expression of ISLR throughout the development with a high increase at 10 weeks for stomach.{{cite journal | vauthors = Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J | display-authors = 6 | title = Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development | journal = Genome Biology | volume = 16 | pages = 126 | date = June 2015 | issue = 1 | pmid = 26076956 | pmc = 4506483 | doi = 10.1186/s13059-015-0690-5 | doi-access = free }} Expression remained notably high to 20 weeks for stomach.

File:In situ Hybridization on Mouse Brain IHC stained for ISLR expression.jpg

In the annotated figure, an in situ Hybridization on a 56-days old male mouse brain (sagittal cut) demonstrated expression in the olfactory areas and hippocampal formation (Figure 4).{{Cite web |title=Gene Detail :: Allen Brain Atlas: Mouse Brain |url=https://mouse.brain-map.org/gene/show/26713 |url-status=live |archive-url=https://web.archive.org/web/20200923222130/https://mouse.brain-map.org/gene/show/26713 |archive-date=23 September 2020 |access-date=2 August 2020 |website=mouse.brain-map.org}}

Based on Protein Abundance Database (PAXdb 4.1), the human protein of ISLR is shown with high protein abundance (ppm value > 1) relative to the whole organism.{{Cite web |title=PAXdb: Protein Abundance Database |url=https://pax-db.org/protein/1843978 |url-status=live |archive-url=https://web.archive.org/web/20200923222129/https://pax-db.org/protein/1843978 |archive-date=23 September 2020 |access-date=2 August 2020 |website=pax-db.org}}

Expression profiling by microarray of ISLR in female human subjects demonstrated overexpression of ISLR in breast lipotransfer white adipose tissue CD34+ cells and significantly lower expression in leukapheresis CD34+ cells.{{cite journal | vauthors = Martin-Padura I, Gregato G, Marighetti P, Mancuso P, Calleri A, Corsini C, Pruneri G, Manzotti M, Lohsiriwat V, Rietjens M, Petit JY, Bertolini F | display-authors = 6 | title = The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34+ progenitors able to promote cancer progression | journal = Cancer Research | volume = 72 | issue = 1 | pages = 325–34 | date = January 2012 | pmid = 22052460 | doi = 10.1158/0008-5472.CAN-11-1739 | doi-access = free }}

Expression profiling by microarray of ISLR in human subjects demonstrated overexpression in non-union skeletal fractures compared to low expression in normal fractures.{{Cite web |title=GEO DataSet Browser |url=https://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS367 |url-status=live |archive-url=https://web.archive.org/web/20200923222126/https://www.ncbi.nlm.nih.gov/sites/GDSbrowser?acc=GDS367 |archive-date=23 September 2020 |access-date=2 August 2020 |website=www.ncbi.nlm.nih.gov}}

Expression profiling by microarray of ISLR in obese female human subjects demonstrated consistent low expression of ISLR in subjects that followed a short-term low-fat hypocaloric diet.{{cite journal | vauthors = Hietaniemi M, Jokela M, Rantala M, Ukkola O, Vuoristo JT, Ilves M, Rysä J, Kesäniemi Y | display-authors = 6 | title = The effect of a short-term hypocaloric diet on liver gene expression and metabolic risk factors in obese women | journal = Nutrition, Metabolism, and Cardiovascular Diseases | volume = 19 | issue = 3 | pages = 177–83 | date = March 2009 | pmid = 18804985 | doi = 10.1016/j.numecd.2008.06.009 | url = https://pubmed.ncbi.nlm.nih.gov/18804985/ | url-status = live | access-date = 2 August 2020 | archive-url = https://web.archive.org/web/20200923222142/https://pubmed.ncbi.nlm.nih.gov/18804985/ | archive-date = 23 September 2020 }}

There is one promoter region in the ISLR gene with a predicted length of 1,912 bp (Figure 5) extracted from Genomatix.{{Cite web |title=genomatix - Google Search |url=https://www.google.com/search?q=genomatix |url-status=live |archive-url=https://web.archive.org/web/20200923222129/https://www.google.com/search?rlz=1C1CHBF_enUS830US830&q=genomatix&sclient=psy-ab |archive-date=23 September 2020 |access-date=3 August 2020 |website=www.google.com}} Additionally, there is a polyadenylation signal at 3,142 bp in the ISLR nucleotide sequence (humans).{{Cite journal |date=29 May 2020 |title=Homo sapiens chromosome 15, GRCh38.p13 Primary Assembly |url=http://www.ncbi.nlm.nih.gov/nuccore/NC_000015.10 |url-status=live |language=en-US |archive-url=https://web.archive.org/web/20161005190136/http://www.ncbi.nlm.nih.gov/nuccore/NC_000015.10 |archive-date=5 October 2016 |access-date=3 August 2020}}

There are six distinct transcription factors that bind onto the promoter region of ISLR from Genomatix predictions: two SMAD factors, sine oculis homeobox (SIX), heat shock factor (HSF), PRDM, Snail, and cell cycles gene homology region (CHR).

Genomatix results predicted more transcription factor binding sites in ISLR with the highest matrix similarity (0.97~0.99) such as:

1. Myeloid zinc finger 1 factor (MZF1)
2. Nuclear factor of activated T-cells
3. Hepatocyte nuclear factor 3 (alpha, beta) (FOXA1, FOXA2)
4. E2F transcription factor 1
5. Eomesodermin, TBR-2 (T-box, brain, 2) (Brachyury gene, mesoderm developmental factor)
6. Homeodomain factor Nkx-2.5/Csx
7. Estrogen-related receptor alpha (secondary DNA binding preference)
8. Early B-cell factor 1 (Neuron specific olfactory factor)
9. Nascent polypeptide-associated complex subunit alpha 1
10. IKAROS family zinc finger 3 (Aiolos)
11. 3' half site of ZTRE motif (zinc transcriptional regulatory element)
12. AREB6 (Atp1a1 regulatory element binding factor 6)

File:Promoter Diagram of ISLR (Human).jpg

The human gene of ISLR is predicted to be targeted by 85 miRNAs in miRDB.{{Cite web |title=miRDB - MicroRNA Target Prediction Database |url=http://mirdb.org/cgi-bin/search.cgi |url-status=live |archive-url=https://web.archive.org/web/20200806230732/http://mirdb.org/cgi-bin/search.cgi |archive-date=6 August 2020 |access-date=3 August 2020 |website=mirdb.org}} The top scoring (>88) miRNAs are has-miR-5197-3p, has-miR-4688, has-miR-3150a-3p, has-miR-16-5p, has-miR-195-5p, has-miR-15a-5p, and has-miR-6763-5p.

RBPmap,{{Cite web |title=RBPmap - Motifs Analysis and Prediction of RNA Binding Proteins |url=http://rbpmap.technion.ac.il/ |url-status=live |archive-url=https://web.archive.org/web/20200222181053/http://rbpmap.technion.ac.il/ |archive-date=22 February 2020 |access-date=3 August 2020 |website=rbpmap.technion.ac.il}} which maps predicted binding sites of RNA binding proteins, showed multiple conserved motifs in evolution relative to the human ISLR mRNA transcript variant 1 sequence such as:

1. BRUNOL6
2. CPEB2 and CPEB4
3. ESRP2
4. FMR1
5. FUS
6. FXR1 and FXR2
7. G3BP2
8. HNRNPA1, HNRNPA1L2, HNRNPA2B1, HNRNPC, HNRNPCL1, HNRNPF, HNRNPH1, HNRNPH2, HNRNPK, HNRNPL, HNRNPM, HNRNPU, HNRPLL.
9. HuR
10. IGF2BP2 and IGF2BP3
11. KHDRBS2
12. LIN28A

Currently, there is one other paralog in humans known as ISLR 2{{Cite web |title=ISLR2 immunoglobulin superfamily containing leucine rich repeat 2 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/57611 |url-status=live |archive-url=https://web.archive.org/web/20200923222139/https://www.ncbi.nlm.nih.gov/gene/57611 |archive-date=23 September 2020 |access-date=2 August 2020 |website=www.ncbi.nlm.nih.gov}} and two paralogous domains: LRRN4 (protein precursor 4) and LRRN4CL (protein precursor 4 C-terminal like).

As of August 2020, there above 190 known orthologs of the ISLR human gene,{{Cite web |title=ISLR orthologs |url=https://www.ncbi.nlm.nih.gov/gene/3671/ortholog/ |url-status=live |archive-url=https://web.archive.org/web/20200923222139/https://www.ncbi.nlm.nih.gov/gene/3671/ortholog/ |archive-date=23 September 2020 |access-date=3 August 2020 |website=NCBI |language=en}} the most distant ortholog and homolog found in Exaiptasia pallida (sea anemone).{{Cite web |title=LOC110239154 uncharacterized LOC110239154 [Exaiptasia diaphana] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/?term=ISLR+Exaiptasia+pallida |url-status=live |archive-url=https://web.archive.org/web/20200923222144/https://www.ncbi.nlm.nih.gov/gene/?term=ISLR+Exaiptasia+pallida |archive-date=23 September 2020 |access-date=3 August 2020 |website=www.ncbi.nlm.nih.gov}} The table below demonstrates the relationships between human ISLR protein characteristics and selected orthologs covering the range from closest related to Homo sapiens to most distant.

There are a total of 284 results from PSIQUIC View{{Cite web |title=PSICQUIC View |url=http://www.ebi.ac.uk/Tools/webservices/psicquic/view/main.xhtml |url-status=live |archive-url=https://web.archive.org/web/20200221212812/http://www.ebi.ac.uk/Tools/webservices/psicquic/view/main.xhtml |archive-date=21 February 2020}} of ISLR (human) that demonstrates its binding to numerous distinct proteins. iRefIndex showed 97 total results with multiple physical association interactions such as ISLR with Rho GTP-family (RHOBTB3), BMP7, Sphingose-1-Phosphate Lyase (SGPL1), Carnitine-acylcarnitine translocase (SLC25A20), Canopy FGF Signaling regulator 3 (CNPY3), and Leishmanolysin-like peptidase (LMLN).{{Cite web |title=PSICQUIC View for ISLR (Human) |url=http://www.ebi.ac.uk/Tools/webservices/psicquic/view/results.xhtml?conversationContext=3 |url-status=live |archive-url=https://web.archive.org/web/20200923222143/http://www.ebi.ac.uk/Tools/webservices/psicquic/view/results.xhtml?conversationContext=3 |archive-date=23 September 2020 |access-date=3 August 2020 |website=www.ebi.ac.uk}} The physical associations were identified with two hybrid pooling approach, affinity chromatography technology, enzymatic study, or anti-tag coimmunoprecipitation. Overall, the results from iRefIndex suggests ISLR to be involved in various mechanisms such as cell migration, transport of different complexes, and metabolism (enzymatic mechanisms). For example, RHOBTB3 is involved in transporting different complexes along pathways such as endosomes to trans Golgi network and Golgi to ER.{{cite journal | vauthors = Espinosa EJ, Calero M, Sridevi K, Pfeffer SR | title = RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport | journal = Cell | volume = 137 | issue = 5 | pages = 938–48 | date = May 2009 | pmid = 19490898 | pmc = 2801561 | doi = 10.1016/j.cell.2009.03.043 }} Furthermore, LMLN has been shown to play a role in cell migration, potentially mitotic progression.{{Cite web |title=LMLN leishmanolysin like peptidase [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/89782 |url-status=live |archive-url=https://web.archive.org/web/20191207160320/https://www.ncbi.nlm.nih.gov/gene/89782 |archive-date=7 December 2019 |access-date=3 August 2020 |website=www.ncbi.nlm.nih.gov}} In terms of metabolism, SGPL1 is involved in the metabolism of sphingolipids.{{cite journal | vauthors = Taylor VA, Stone HK, Schuh MP, Zhao X, Setchell KD, Erkan E | title = Disarranged Sphingolipid Metabolism From Sphingosine-1-Phosphate Lyase Deficiency Leads to Congenital Nephrotic Syndrome | journal = Kidney International Reports | volume = 4 | issue = 12 | pages = 1763–1769 | date = December 2019 | pmid = 31844815 | pmc = 6895586 | doi = 10.1016/j.ekir.2019.07.018 }}

Based on the previous results from iRefindex that indicated physical associations between ISLR and other proteins, two different interactions were identified with distinct strains of coronavirus. An interaction with orf1ab polyprotein of the human coronavirus strain HKU1(HCov-HKU1) was shown in physical association with ISLR through the two hybrid pooling approach, where ISLR is indicated as "prey" and the orf1ab polyprotein is indicated as "bait".{{cite journal | vauthors = Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, Stellberger T, von Dall'Armi E, Herzog P, Kallies S, Niemeyer D, Ditt V, Kuri T, Züst R, Pumpor K, Hilgenfeld R, Schwarz F, Zimmer R, Steffen I, Weber F, Thiel V, Herrler G, Thiel HJ, Schwegmann-Wessels C, Pöhlmann S, Haas J, Drosten C, von Brunn A | display-authors = 6 | title = The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors | journal = PLOS Pathogens | volume = 7 | issue = 10 | pages = e1002331 | date = October 2011 | pmid = 22046132 | pmc = 3203193 | doi = 10.1371/journal.ppat.1002331 | doi-access = free }}

There is another detected interaction of ISLR and Human SARS coronavirus through direct contact based on the two hybrid pooling approach.

The delivery of ISLR-expressing lentivirus into a tumor stroma suppressed the growth of tumors in pancreatic ductal adenocarcinoma (PDAC).{{cite journal | vauthors = Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, Ando K, Weng L, Ishihara S, Ponik SM, Conklin MW, Haga H, Nagasaka A, Miyata T, Matsuyama M, Kobayashi T, Fujii T, Yamada S, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M | display-authors = 6 | title = Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis | journal = Cancer Research | volume = 79 | issue = 20 | pages = 5367–5381 | date = October 2019 | pmid = 31439548 | doi = 10.1158/0008-5472.CAN-19-0454 | doi-access = free }} In PDAC, low expression of ISLR (Meflin) was associated with aggressive tumors, characterized by straight collagen fibers in the stroma. Regarding tumorigenesis in IBD patients, a study investigated the Hippo signaling pathway in intestinal regeneration of epithelial cells.{{Cite book | vauthors = Xu J, Tang Y, Sheng X, Tian Y, Deng M, Du S, Lv C, Song Y, Lou P | display-authors = 6 | url = https://www.researchgate.net/publication/335306842 |title=Stromal ISLR promotes intestinal regeneration and cancer by suppressing epithelial Hippo signaling |date=20 August 2019 |access-date=3 August 2020 |archive-url=https://web.archive.org/web/20200923222141/https://www.researchgate.net/publication/335306842_Stromal_ISLR_promotes_intestinal_regeneration_and_cancer_by_suppressing_epithelial_Hippo_signaling |archive-date=23 September 2020 |url-status=live}} ETS1, an oncogenic transcription factor in stromal cells, induced the expression of ISLR protein which inhibited Hippo signaling, thus promoting intestinal regeneration. In mice, it was demonstrated that deletion of ISLR in stromal cells can suppress tumorigenesis in the intestine. For the ISLR 2 paralog, a study demonstrated that congenital hydrocephalus, arthrogryposis, and abdominal distension is associated with an autosomal recessive knockout on the phenotype of ISLR 2 in a multiplex consanguineous family.{{cite journal | vauthors = Alazami AM, Maddirevula S, Seidahmed MZ, Albhlal LA, Alkuraya FS | title = A novel ISLR2-linked autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension | journal = Human Genetics | volume = 138 | issue = 1 | pages = 105–107 | date = January 2019 | pmid = 30483960 | doi = 10.1007/s00439-018-1963-3 | url = https://pubmed.ncbi.nlm.nih.gov/30483960/ | url-status = live | access-date = 3 August 2020 | s2cid = 53781275 | archive-url = https://web.archive.org/web/20200923222144/https://pubmed.ncbi.nlm.nih.gov/30483960/ | archive-date = 23 September 2020 }} ISLR 2 encodes a protein that plays a role in axon guidance in brain development, hence, unveiling potential links to certain congenital neurological disorders.

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Category:Genes on human chromosome 15