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'''Integrin-linked kinase''' is an [[enzyme]] that in humans is encoded by the ILK [[gene]] involved with [[integrin]]-mediated [[signal transduction]]. It is a 59kDa protein originally identified in a yeast-two hybrid screen with integrin β1 as the bait protein.<ref name = "Hannigan_1996" /> Since its discovery, ILK has been associated with multiple cellular functions including cell [[cell migration|migration]], [[cell proliferation|proliferation]], and [[cell adhesion|adhesion]].
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Integrin-linked kinases (ILKs) are a subfamily of Raf-like kinases (RAF). ILK structure is comprised of three features: 5 [[ankyrin]] repeats in the N-terminus, [[Phosphoinositide]] binding motif and extreme N-terminus of [[kinase]] catalytic domain.<ref name="Dedhar_1999">{{cite journal | vauthors = Dedhar S, Williams B, Hannigan G | title = Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling | journal = Trends in Cell Biology | volume = 9 | issue = 8 | pages = 319–23 | year = 1999 | pmid = 10407411 | doi = 10.1016/s0962-8924(99)01612-8 }}</ref> Integrins lack enzymatic activity and depend on adapters to signal proteins.<ref name="Dedhar_1999" /> ILK is linked to beta-1 and beta-3 integrin cytoplasmic domains and is one of the best described integrins.<ref name="Widmaier_2012">{{cite journal | vauthors = Widmaier M, Rognoni E, Radovanac K, Azimifar SB, Fässler R | title = Integrin-linked kinase at a glance | journal = Journal of Cell Science | volume = 125 | issue = Pt 8 | pages = 1839–43 | year = 2012 | pmid = 22637643 | doi = 10.1242/jcs.093864 }}</ref> Although first described as a serine/threonine kinase by Hannigan,<ref name="Hannigan_1996">{{cite journal | vauthors = Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S | title = Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase | journal = Nature | volume = 379 | issue = 6560 | pages = 91–6 | year = 1996 | pmid = 8538749 | doi = 10.1038/379091a0 }}</ref> important motifs of ILK kinases are still uncharacterized.<ref name="Widmaier_2012" /> ILK is thought to have a roll in development regulation and tissue homeostasis, however it was found that in flies, worms and mice ILK activity isn’t required to regulate these processes.<ref name="Widmaier_2012" />
{{GNF_Protein_box
| image =
| image_source = 
| PDB =
| Name = Integrin-linked kinase
| HGNCid = 6040
| Symbol = ILK
| AltSymbols =; DKFZp686F1765; P59
| OMIM = 602366
| ECnumber =
| Homologene = 3318
| MGIid = 1195267
| GeneAtlas_image1 = PBB_GE_ILK_201234_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0004713 |text = protein-tyrosine kinase activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016301 |text = kinase activity}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005925 |text = focal adhesion}}  
| Process = {{GNF_GO|id=GO:0001658 |text = ureteric bud branching}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007160 |text = cell-matrix adhesion}} {{GNF_GO|id=GO:0007229 |text = integrin-mediated signaling pathway}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0045197 |text = establishment and/or maintenance of epithelial cell polarity}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3611
    | Hs_Ensembl = ENSG00000166333
    | Hs_RefseqProtein = NP_001014794
    | Hs_RefseqmRNA = NM_001014794
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 6581540
    | Hs_GenLoc_end = 6588673
    | Hs_Uniprot = Q13418
    | Mm_EntrezGene = 16202
    | Mm_Ensembl = ENSMUSG00000030890
    | Mm_RefseqmRNA = NM_010562
    | Mm_RefseqProtein = NP_034692
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 105610473
    | Mm_GenLoc_end = 105616745
    | Mm_Uniprot = O55222
  }}
}}
'''Integrin-linked kinase''' (ILK) is a 59kDa protein originally identified while conducting a yeast-two hybrid screen with integrin β1 as the bait protein (Hannigan et al., 1996).  Since its discovery, ILK has been associated with multiple cellular functions including cell migration, cell proliferation, cell-adhesions, signal transduction


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Animal ILKs have been linked to the pinch- parvin complex which control muscle development.<ref name="Widmaier_2012" /> Mice lacking ILK were embryonic lethal due to lack of organized muscle cell development.<ref name="Widmaier_2012" /> In mammals ILK lacks catalytic activity but supports scaffolding protein functions for [[focal adhesion]]s.<ref name="Widmaier_2012" />  In plants, ILKs signal complexes to focal adhesion sites.<ref name="Popescu_2017" /> ILKs of plants contain multiple ILK genes. Unlike animals that contain few ILK genes<ref name="Popescu_2017" /> ILKs have been found to possess oncogenic properties. ILKs control the activity of serine/threonine phosphatases.<ref name="Widmaier_2012" />
{{PBB_Summary
| section_title =
| summary_text = Transduction of [[extracellular matrix]] signals through [[integrins]] influences intracellular and extracellular functions, and appears to require interaction of integrin [[cytoplasmic]] domains with cellular proteins. Integrin-linked kinase (ILK), interacts with the cytoplasmic domain of beta-1 integrin. This gene encodes a [[serine]]/[[threonine]] protein [[kinase]] with 4 ankyrin-like repeats, which associates with the cytoplasmic domain of beta integrins and acts as a proximal receptor kinase regulating integrin-mediated signal transduction. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.<ref>{{cite web | title = Entrez Gene: ILK integrin-linked kinase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3611| accessdate = }}</ref>
}}


In 2008, ILK was found to localize to the [[centrosome]] and regulate [[mitotic spindle]] organization. <ref>{{cite web | title = Fielding A, Dobreva I, ''et al.'' (2008). "Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization.". ''J. Cell Biol.'' 180(4):681-9.| url = http://www.ncbi.nlm.nih.gov/pubmed/18283114| accessdate = }}</ref>
== Principle Features ==


Transduction of [[extracellular matrix]] signals through [[integrins]] influences intracellular and extracellular functions, and appears to require interaction of integrin [[cytoplasmic]] domains with cellular proteins. Integrin-linked kinase (ILK), interacts with the [[cytoplasmic]] domain of beta-1 integrin. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.<ref>{{cite web |title=Entrez Gene: ILK integrin-linked kinase |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3611 }}</ref> Recent results showed that the C-terminal kinase domain is actually a pseudo-kinase with adaptor function.<ref>{{cite journal | vauthors = Lange A, Wickström SA, Jakobson M, Zent R, Sainio K, Fässler R | title = Integrin-linked kinase is an adaptor with essential functions during mouse development | journal = Nature | volume = 461 | issue = 7266 | pages = 1002–6 | date = October 2009 | pmid = 19829382 | doi = 10.1038/nature08468 }}</ref><ref>{{cite journal | vauthors = Fukuda K, Gupta S, Chen K, Wu C, Qin J | title = The pseudoactive site of ILK is essential for its binding to alpha-Parvin and localization to focal adhesions | journal = Molecular Cell | volume = 36 | issue = 5 | pages = 819–30 | date = December 2009 | pmid = 20005845 | pmc = 2796127 | doi = 10.1016/j.molcel.2009.11.028 }}</ref><ref>{{cite journal | vauthors = Qin J, Wu C | title = ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling | journal = Current Opinion in Cell Biology | volume = 24 | issue = 5 | pages = 607–13 | date = October 2012 | pmid = 22763012 | pmc = 3467332 | doi = 10.1016/j.ceb.2012.06.003 }}</ref>


==References==
In 2008, ILK was found to localize to the [[centrosome]] and regulate [[mitotic spindle]] organization.<ref>{{cite journal | vauthors = Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S | title = Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization | journal = The Journal of Cell Biology | volume = 180 | issue = 4 | pages = 681–9 | date = February 2008 | pmid = 18283114 | pmc = 2265580 | doi = 10.1083/jcb.200710074 }}</ref>
{{reflist|2}}
 
==Further reading==
Integrin-linked kinase has been shown to [[Protein-protein interaction|interact]] with:
{{refbegin | 2}}
{{div col|colwidth=20em}}
{{PBB_Further_reading
* [[ACP6]],<ref name = pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | issue =  | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}</ref>
| citations =
* [[AKT1]],<ref name = pmid11825911>{{cite journal | vauthors = Barry FA, Gibbins JM | title = Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI | journal = The Journal of Biological Chemistry | volume = 277 | issue = 15 | pages = 12874–8 | date = April 2002 | pmid = 11825911 | doi = 10.1074/jbc.M200482200 }}</ref><ref name = pmid9736715>{{cite journal | vauthors = Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S | title = Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 19 | pages = 11211–6 | date = September 1998 | pmid = 9736715 | pmc = 21621 | doi = 10.1073/pnas.95.19.11211 }}</ref><ref name = pmid11313365>{{cite journal | vauthors = Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S | title = Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 29 | pages = 27462–9 | date = July 2001 | pmid = 11313365 | doi = 10.1074/jbc.M102940200 }}</ref>
*{{cite journal  | author=Dedhar S |title=Cell-substrate interactions and signaling through ILK. |journal=Curr. Opin. Cell Biol. |volume=12 |issue= 2 |pages= 250-6 |year= 2000 |pmid= 10712922 |doi= }}
* [[ILKAP]],<ref name = pmid11331582>{{cite journal | vauthors = Leung-Hagesteijn C, Mahendra A, Naruszewicz I, Hannigan GE | title = Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1 | journal = The EMBO Journal | volume = 20 | issue = 9 | pages = 2160–70 | date = May 2001 | pmid = 11331582 | pmc = 125446 | doi = 10.1093/emboj/20.9.2160 }}</ref>  and
*{{cite journal  | author=Persad S, Dedhar S |title=The role of integrin-linked kinase (ILK) in cancer progression. |journal=Cancer Metastasis Rev. |volume=22 |issue= 4 |pages= 375-84 |year= 2004 |pmid= 12884912 |doi=  }}
* [[LIMS1]],<ref name = pmid10022929>{{cite journal | vauthors = Tu Y, Li F, Goicoechea S, Wu C | title = The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells | journal = Molecular and Cellular Biology | volume = 19 | issue = 3 | pages = 2425–34 | date = March 1999 | pmid = 10022929 | pmc = 84035 | doi = 10.1128/mcb.19.3.2425 }}</ref><ref name = pmid12167643>{{cite journal | vauthors = Zhang Y, Chen K, Guo L, Wu C | title = Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1-ILK interaction, cell spreading, and migration | journal = The Journal of Biological Chemistry | volume = 277 | issue = 41 | pages = 38328–38 | date = October 2002 | pmid = 12167643 | doi = 10.1074/jbc.M205576200 }}</ref>
*{{cite journal | author=Srivastava D, Yu S |title=Stretching to meet needs: integrin-linked kinase and the cardiac pump. |journal=Genes Dev. |volume=20 |issue= 17 |pages= 2327-31 |year= 2006 |pmid= 16951248 |doi= 10.1101/gad.1472506 }}
{{Div col end}}
*{{cite journal | author=Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, ''et al.'' |title=Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. |journal=Nature |volume=379 |issue= 6560 |pages= 91-6 |year= 1996 |pmid= 8538749 |doi= 10.1038/379091a0 }}
 
*{{cite journal | author=Hannigan GE, Bayani J, Weksberg R, ''et al.'' |title=Mapping of the gene encoding the integrin-linked kinase, ILK, to human chromosome 11p15.5-p15.4. |journal=Genomics |volume=42 |issue= 1 |pages= 177-9 |year= 1997 |pmid= 9177792 |doi= 10.1006/geno.1997.4719 }}
== Function of Plant ILK1 ==
*{{cite journal | author=Li F, Liu J, Mayne R, Wu C |title=Identification and characterization of a mouse protein kinase that is highly homologous to human integrin-linked kinase. |journal=Biochim. Biophys. Acta |volume=1358 |issue= 3 |pages= 215-20 |year= 1997 |pmid= 9366252 |doi= }}
 
*{{cite journal | author=Delcommenne M, Tan C, Gray V, ''et al.'' |title=Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 19 |pages= 11211-6 |year= 1998 |pmid= 9736715 |doi= }}
ILKs function by interacting with the many transmembrane receptors to regulate different signaling cascades.<ref name="Hannigan_1996" /> ILK1 has been found in the root system of most plants where they are co-localized on the plasma membrane and endoplasmic reticulum where they transport ions across the plasma membrane<ref name="Popescu_2017">{{cite journal | vauthors = Popescu SC, Brauer EK, Dimlioglu G, Popescu GV | title = Insights into the Structure, Function, and Ion-Mediated Signaling Pathways Transduced by Plant Integrin-Linked Kinases | journal = Frontiers in Plant Science | volume = 8 | pages = 376 | date = 2017 | pmid = 28421082 | doi = 10.3389/fpls.2017.00376 }}</ref> ILK1 is responsible for the control of osmotic and salt stress, control of the uptake of nutrients based on availability and pathogen detection.<ref name="Brauer_2016">{{Cite journal | last = Brauer | first = Elizabeth | name-list-format = vanc | date = June 2016|title=The Raf-like Kinsase ILK1 and the High Affinity K+ Transporter HAK5 Are Required for Innate Immunity and Abiotic Stress Response|url=http://www.scopus.com/inward/record.url?eid=2-s2.0-85011709981&partnerID=MN8TOARS|journal=Plant Physiology|volume=171|pages=1470–1484|via=American Society of Plant Biologists}}</ref>
*{{cite journal | author=Chung DH, Lee JI, Kook MC, ''et al.'' |title=ILK (beta1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing's sarcoma and primitive neuroectodermal tumour. |journal=Virchows Arch. |volume=433 |issue= 2 |pages= 113-7 |year= 1998 |pmid= 9737788 |doi= }}
 
*{{cite journal  | author=Tu Y, Li F, Goicoechea S, Wu C |title=The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. |journal=Mol. Cell. Biol. |volume=19 |issue= 3 |pages= 2425-34 |year= 1999 |pmid= 10022929 |doi= }}
=== Osmotic and salt stress ===
*{{cite journal  | author=Feng J, Ito M, Ichikawa K, ''et al.'' |title=Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. |journal=J. Biol. Chem. |volume=274 |issue= 52 |pages= 37385-90 |year= 2000 |pmid= 10601309 |doi= }}
 
*{{cite journal  | author=Janji B, Melchior C, Vallar L, Kieffer N |title=Cloning of an isoform of integrin-linked kinase (ILK) that is upregulated in HT-144 melanoma cells following TGF-beta1 stimulation. |journal=Oncogene |volume=19 |issue= 27 |pages= 3069-77 |year= 2000 |pmid= 10871859 |doi= 10.1038/sj.onc.1203640 }}
ILK1 is linked to hyperosmotic stress sensitivity.<ref name="Brauer_2016" /> ILK1 reduced salt stress in seedlings placed in solution with increased concentrations of salt.<ref name="Popescu_2017" /> ILK1 concentrations remain fairly constant throughout development regardless of a high salt exposure.<ref name="Brauer_2016" /> Previously, it was believed that K<sup>+</sup> accumulation was reduced in increased salt concentration.<ref name="Alemán_2011">{{cite journal | vauthors = Alemán F, Nieves-Cordones M, Martínez V, Rubio F | title = Root K(+) acquisition in plants: the Arabidopsis thaliana model | journal = Plant & Cell Physiology | volume = 52 | issue = 9 | pages = 1603–12 | year = 2011 | pmid = 21771865 | doi = 10.1093/pcp/pcr096 }}</ref> K<sup>+</sup> homeostasis is not affected in high salt concentrations. During periods of high salt stress, K<sup>+</sup> concentrations in the presence of ILK1 was maintained at the existing level. Potassium transport is required for flg22 root growth inhibition and potassium transport was affected by flg22.<ref name="Brauer_2016" />
*{{cite journal | author=Velyvis A, Yang Y, Wu C, Qin J |title=Solution structure of the focal adhesion adaptor PINCH LIM1 domain and characterization of its interaction with the integrin-linked kinase ankyrin repeat domain. |journal=J. Biol. Chem. |volume=276 |issue= 7 |pages= 4932-9 |year= 2001 |pmid= 11078733 |doi= 10.1074/jbc.M007632200 }}
 
*{{cite journal | author=Matsumoto M, Ogawa W, Hino Y, ''et al.'' |title=Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C. |journal=J. Biol. Chem. |volume=276 |issue= 17 |pages= 14400-6 |year= 2001 |pmid= 11278835 |doi= 10.1074/jbc.M011093200 }}
Potassium levels modulate the activation of flg22, a flagellin peptide composed of 22 amino acids that triggers pathogen-associated molecular patterns (PAMPs). [[Pathogen-associated molecular pattern|PAMPs]] functions by activating regulators of bacterial pathogen alert system.<ref name="Brauer_2016" /><ref name="Chinchilla_2006">{{cite journal | vauthors = Chinchilla D, Bauer Z, Regenass M, Boller T, Felix G | title = The Arabidopsis receptor kinase FLS2 binds flg22 and determines the specificity of flagellin perception | journal = The Plant Cell | volume = 18 | issue = 2 | pages = 465–76 | year = 2006 | pmid = 16377758 | pmc = 1356552 | doi = 10.1105/tpc.105.036574 }}</ref> Ion concentration levels of Mn<sup>2+</sup>, Mg<sup>2+</sup>, S and Ca<sup>2+</sup> were also affected after PAMP regulators were mobilized.<ref name="Brauer_2016" />
*{{cite journal  | author=Nikolopoulos SN, Turner CE |title=Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. |journal=J. Biol. Chem. |volume=276 |issue= 26 |pages= 23499-505 |year= 2001 |pmid= 11304546 |doi= 10.1074/jbc.M102163200 }}
 
*{{cite journal  | author=Persad S, Attwell S, Gray V, ''et al.'' |title=Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. |journal=J. Biol. Chem. |volume=276 |issue= 29 |pages= 27462-9 |year= 2001 |pmid= 11313365 |doi= 10.1074/jbc.M102940200 }}
=== Nutrient uptake ===
*{{cite journal | author=Tu Y, Huang Y, Zhang Y, ''et al.'' |title=A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading. |journal=J. Cell Biol. |volume=153 |issue= 3 |pages= 585-98 |year= 2001 |pmid= 11331308 |doi=  }}
Potassium (K<sup>+</sup>) is responsible for osmoregulation, membrane potential maintenance and turgor pressure of plant cells which in turn mediates stomata movement and growth of tubules within the plant.<ref name="Wang_2017" /> Photosynthesis and other metabolic pathways are controlled by potassium.<ref name="Wang_2017">{{cite journal | vauthors = Wang Y, Wu WH | title = Regulation of potassium transport and signaling in plants | journal = Current Opinion in Plant Biology | volume = 39 | pages = 123–128 | date = October 2017 | pmid = 28710919 | doi = 10.1016/j.pbi.2017.06.006 | url = http://dx.doi.org/10.1016/j.pbi.2017.06.006 }}</ref> When sufficient K<sup>+</sup> uptake is not met, PAMPs are activated. Calmodulins, specifically CML9, have appeared as important genes to interact with ILK1 and regulate potassium levels within the cell. While [[Calmodulin|CLM9]] primarily regulates Ca<sup>2+</sup> it is linked to a yet identified K<sup>+</sup>/Ca<sup>2+</sup> influx channel.<ref name="Popescu_2017" /> While interactions are known to occur between CML9 and ILK1, ILK1 Is not a direct phosphorylation target of CML9. With the addition of CML9, autophosphorylation of ILK1 is diminished, the present irrespective of calcium available for uptake.
*{{cite journal  | author=Leung-Hagesteijn C, Mahendra A, Naruszewicz I, Hannigan GE |title=Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1. |journal=EMBO J. |volume=20 |issue= 9 |pages= 2160-70 |year= 2001 |pmid= 11331582 |doi= 10.1093/emboj/20.9.2160 }}
[[File:Plant ILK Structural Features.jpg|thumb|A) Full length protein sequence of Arabidopsis. B) 3D structures of ILK repeates. C) N-terminal is blue C-terminal is red. Shows the succession of secondary elements. D) Amino acid sequence of ILK.]]
*{{cite journal  | author=Yamaji S, Suzuki A, Sugiyama Y, ''et al.'' |title=A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction. |journal=J. Cell Biol. |volume=153 |issue= 6 |pages= 1251-64 |year= 2001 |pmid= 11402068 |doi=  }}
ILK1 is also affected by presence or absence of Manganese (Mn<sup>2+</sup>). Autophosphorylation and substrate phosphorylation occurred when exposed to both Mn<sup>2+</sup> and Mg<sup>2+.</sup> Mn<sup>2+</sup> and was dose dependent where Mg<sup>2+</sup> was not. Specific ILK autophosphorylation sites were found in the presence of Mn<sup>2+</sup> but not in the presence of Mg<sup>2+</sup> which supports the ILK1 dependent phosphorylation suggested above.<ref name="Popescu_2017" /> Mass spectrometry revealed no other kinases were present to trigger this response.
*{{cite journal | author=Chen R, Kim O, Yang J, ''et al.'' |title=Regulation of Akt/PKB activation by tyrosine phosphorylation. |journal=J. Biol. Chem. |volume=276 |issue= 34 |pages= 31858-62 |year= 2001 |pmid= 11445557 |doi= 10.1074/jbc.C100271200 }}
 
}}
=== Pathogen detection ===
*{{cite journal | author=Fielding A, Dobreva I, McDonald PC, ''et al.'' |title=Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization. |journal=J. Cell Biol. |volume=180 |issue= 4 |pages= 681-9 |year= 2008 |pmid= 18283114 |doi= 10.1083/jcb.200710074 }}
 
ILK1 has been found to promote resistance in bacterial pathogens.<ref name="Popescu_2017" /> ILK1 is required for flg22 sensitivity in seedlings. A catalytically inactive version of ILK1 was compared with catalytically active versions of ILK1 to see the level of resistance when challenged with bacterial pathogens. Plants inoculated with inactive ILK1 were more susceptible to bacterial infection than active ILK1 suggesting that ILK1 is needed for bacterial pathogen detection. While ILK1 is involved in bacterial pathogen detection it is not used for effect induced defenses.<ref name="Brauer_2016" />
 
ILK1 increases PAMP response and basal immunity through phosphorylation of MPK3 and MPK6 and operates independently in reactive oxygen species ([[Reactive oxygen species|ROS]]) production. High Affinity Potassium uptake mediators such as [[HAK5]] have also been found to be integral in the signaling of flg22.<ref name="Brauer_2016" /> HAK5 function when potassium levels are low.<ref name="Brauer_2016" /> Flg22 has been shown to depolarize the cell’s plasma membrane with HAK5 and ILK1 working together to mediate ion homeostasis to assist with both short and long term actions such as growth and suppression thereof.<ref name="Brauer_2016" />
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Dedhar S | title = Cell-substrate interactions and signaling through ILK | journal = Current Opinion in Cell Biology | volume = 12 | issue = 2 | pages = 250–6 | date = April 2000 | pmid = 10712922 | doi = 10.1016/S0955-0674(99)00083-6 }}
* {{cite journal | vauthors = Persad S, Dedhar S | title = The role of integrin-linked kinase (ILK) in cancer progression | journal = Cancer Metastasis Reviews | volume = 22 | issue = 4 | pages = 375–84 | date = December 2003 | pmid = 12884912 | doi = 10.1023/A:1023777013659 }}
* {{cite journal | vauthors = Srivastava D, Yu S | title = Stretching to meet needs: integrin-linked kinase and the cardiac pump | journal = Genes & Development | volume = 20 | issue = 17 | pages = 2327–31 | date = September 2006 | pmid = 16951248 | doi = 10.1101/gad.1472506 }}
* {{cite journal | vauthors = Hannigan GE, Bayani J, Weksberg R, Beatty B, Pandita A, Dedhar S, Squire J | title = Mapping of the gene encoding the integrin-linked kinase, ILK, to human chromosome 11p15.5-p15.4 | journal = Genomics | volume = 42 | issue = 1 | pages = 177–9 | date = May 1997 | pmid = 9177792 | doi = 10.1006/geno.1997.4719 }}
* {{cite journal | vauthors = Li F, Liu J, Mayne R, Wu C | title = Identification and characterization of a mouse protein kinase that is highly homologous to human integrin-linked kinase | journal = Biochimica et Biophysica Acta | volume = 1358 | issue = 3 | pages = 215–20 | date = October 1997 | pmid = 9366252 | doi = 10.1016/S0167-4889(97)00089-X }}
* {{cite journal | vauthors = Chung DH, Lee JI, Kook MC, Kim JR, Kim SH, Choi EY, Park SH, Song HG | title = ILK (beta1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing's sarcoma and primitive neuroectodermal tumour | journal = Virchows Archiv | volume = 433 | issue = 2 | pages = 113–7 | date = August 1998 | pmid = 9737788 | doi = 10.1007/s004280050225 }}
* {{cite journal | vauthors = Tu Y, Li F, Goicoechea S, Wu C | title = The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells | journal = Molecular and Cellular Biology | volume = 19 | issue = 3 | pages = 2425–34 | date = March 1999 | pmid = 10022929 | pmc = 84035 | doi = 10.1128/mcb.19.3.2425 }}
* {{cite journal | vauthors = Feng J, Ito M, Ichikawa K, Isaka N, Nishikawa M, Hartshorne DJ, Nakano T | title = Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 52 | pages = 37385–90 | date = December 1999 | pmid = 10601309 | doi = 10.1074/jbc.274.52.37385 }}
* {{cite journal | vauthors = Janji B, Melchior C, Vallar L, Kieffer N | title = Cloning of an isoform of integrin-linked kinase (ILK) that is upregulated in HT-144 melanoma cells following TGF-beta1 stimulation | journal = Oncogene | volume = 19 | issue = 27 | pages = 3069–77 | date = June 2000 | pmid = 10871859 | doi = 10.1038/sj.onc.1203640 }}
* {{cite journal | vauthors = Velyvis A, Yang Y, Wu C, Qin J | title = Solution structure of the focal adhesion adaptor PINCH LIM1 domain and characterization of its interaction with the integrin-linked kinase ankyrin repeat domain | journal = The Journal of Biological Chemistry | volume = 276 | issue = 7 | pages = 4932–9 | date = February 2001 | pmid = 11078733 | doi = 10.1074/jbc.M007632200 }}
* {{cite journal | vauthors = Matsumoto M, Ogawa W, Hino Y, Furukawa K, Ono Y, Takahashi M, Ohba M, Kuroki T, Kasuga M | title = Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C | journal = The Journal of Biological Chemistry | volume = 276 | issue = 17 | pages = 14400–6 | date = April 2001 | pmid = 11278835 | doi = 10.1074/jbc.M011093200 }}
* {{cite journal | vauthors = Nikolopoulos SN, Turner CE | title = Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions | journal = The Journal of Biological Chemistry | volume = 276 | issue = 26 | pages = 23499–505 | date = June 2001 | pmid = 11304546 | doi = 10.1074/jbc.M102163200 }}
* {{cite journal | vauthors = Tu Y, Huang Y, Zhang Y, Hua Y, Wu C | title = A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading | journal = The Journal of Cell Biology | volume = 153 | issue = 3 | pages = 585–98 | date = April 2001 | pmid = 11331308 | pmc = 2190577 | doi = 10.1083/jcb.153.3.585 }}
* {{cite journal | vauthors = Yamaji S, Suzuki A, Sugiyama Y, Koide Y, Yoshida M, Kanamori H, Mohri H, Ohno S, Ishigatsubo Y | title = A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction | journal = The Journal of Cell Biology | volume = 153 | issue = 6 | pages = 1251–64 | date = June 2001 | pmid = 11402068 | pmc = 2192033 | doi = 10.1083/jcb.153.6.1251 }}
* {{cite journal | vauthors = Chen R, Kim O, Yang J, Sato K, Eisenmann KM, McCarthy J, Chen H, Qiu Y | title = Regulation of Akt/PKB activation by tyrosine phosphorylation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 34 | pages = 31858–62 | date = August 2001 | pmid = 11445557 | doi = 10.1074/jbc.C100271200 }}


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[[Category:Proteins]]
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Revision as of 20:07, 4 December 2017

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Integrin-linked kinase is an enzyme that in humans is encoded by the ILK gene involved with integrin-mediated signal transduction. It is a 59kDa protein originally identified in a yeast-two hybrid screen with integrin β1 as the bait protein.[1] Since its discovery, ILK has been associated with multiple cellular functions including cell migration, proliferation, and adhesion.

Integrin-linked kinases (ILKs) are a subfamily of Raf-like kinases (RAF). ILK structure is comprised of three features: 5 ankyrin repeats in the N-terminus, Phosphoinositide binding motif and extreme N-terminus of kinase catalytic domain.[2] Integrins lack enzymatic activity and depend on adapters to signal proteins.[2] ILK is linked to beta-1 and beta-3 integrin cytoplasmic domains and is one of the best described integrins.[3] Although first described as a serine/threonine kinase by Hannigan,[1] important motifs of ILK kinases are still uncharacterized.[3] ILK is thought to have a roll in development regulation and tissue homeostasis, however it was found that in flies, worms and mice ILK activity isn’t required to regulate these processes.[3]

Animal ILKs have been linked to the pinch- parvin complex which control muscle development.[3] Mice lacking ILK were embryonic lethal due to lack of organized muscle cell development.[3] In mammals ILK lacks catalytic activity but supports scaffolding protein functions for focal adhesions.[3] In plants, ILKs signal complexes to focal adhesion sites.[4] ILKs of plants contain multiple ILK genes. Unlike animals that contain few ILK genes[4] ILKs have been found to possess oncogenic properties. ILKs control the activity of serine/threonine phosphatases.[3]

Principle Features

Transduction of extracellular matrix signals through integrins influences intracellular and extracellular functions, and appears to require interaction of integrin cytoplasmic domains with cellular proteins. Integrin-linked kinase (ILK), interacts with the cytoplasmic domain of beta-1 integrin. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.[5] Recent results showed that the C-terminal kinase domain is actually a pseudo-kinase with adaptor function.[6][7][8]

In 2008, ILK was found to localize to the centrosome and regulate mitotic spindle organization.[9]

Integrin-linked kinase has been shown to interact with:

Function of Plant ILK1

ILKs function by interacting with the many transmembrane receptors to regulate different signaling cascades.[1] ILK1 has been found in the root system of most plants where they are co-localized on the plasma membrane and endoplasmic reticulum where they transport ions across the plasma membrane[4] ILK1 is responsible for the control of osmotic and salt stress, control of the uptake of nutrients based on availability and pathogen detection.[17]

Osmotic and salt stress

ILK1 is linked to hyperosmotic stress sensitivity.[17] ILK1 reduced salt stress in seedlings placed in solution with increased concentrations of salt.[4] ILK1 concentrations remain fairly constant throughout development regardless of a high salt exposure.[17] Previously, it was believed that K+ accumulation was reduced in increased salt concentration.[18] K+ homeostasis is not affected in high salt concentrations. During periods of high salt stress, K+ concentrations in the presence of ILK1 was maintained at the existing level. Potassium transport is required for flg22 root growth inhibition and potassium transport was affected by flg22.[17]

Potassium levels modulate the activation of flg22, a flagellin peptide composed of 22 amino acids that triggers pathogen-associated molecular patterns (PAMPs). PAMPs functions by activating regulators of bacterial pathogen alert system.[17][19] Ion concentration levels of Mn2+, Mg2+, S and Ca2+ were also affected after PAMP regulators were mobilized.[17]

Nutrient uptake

Potassium (K+) is responsible for osmoregulation, membrane potential maintenance and turgor pressure of plant cells which in turn mediates stomata movement and growth of tubules within the plant.[20] Photosynthesis and other metabolic pathways are controlled by potassium.[20] When sufficient K+ uptake is not met, PAMPs are activated. Calmodulins, specifically CML9, have appeared as important genes to interact with ILK1 and regulate potassium levels within the cell. While CLM9 primarily regulates Ca2+ it is linked to a yet identified K+/Ca2+ influx channel.[4] While interactions are known to occur between CML9 and ILK1, ILK1 Is not a direct phosphorylation target of CML9. With the addition of CML9, autophosphorylation of ILK1 is diminished, the present irrespective of calcium available for uptake.

File:Plant ILK Structural Features.jpg
A) Full length protein sequence of Arabidopsis. B) 3D structures of ILK repeates. C) N-terminal is blue C-terminal is red. Shows the succession of secondary elements. D) Amino acid sequence of ILK.

ILK1 is also affected by presence or absence of Manganese (Mn2+). Autophosphorylation and substrate phosphorylation occurred when exposed to both Mn2+ and Mg2+. Mn2+ and was dose dependent where Mg2+ was not. Specific ILK autophosphorylation sites were found in the presence of Mn2+ but not in the presence of Mg2+ which supports the ILK1 dependent phosphorylation suggested above.[4] Mass spectrometry revealed no other kinases were present to trigger this response.

Pathogen detection

ILK1 has been found to promote resistance in bacterial pathogens.[4] ILK1 is required for flg22 sensitivity in seedlings. A catalytically inactive version of ILK1 was compared with catalytically active versions of ILK1 to see the level of resistance when challenged with bacterial pathogens. Plants inoculated with inactive ILK1 were more susceptible to bacterial infection than active ILK1 suggesting that ILK1 is needed for bacterial pathogen detection. While ILK1 is involved in bacterial pathogen detection it is not used for effect induced defenses.[17]

ILK1 increases PAMP response and basal immunity through phosphorylation of MPK3 and MPK6 and operates independently in reactive oxygen species (ROS) production. High Affinity Potassium uptake mediators such as HAK5 have also been found to be integral in the signaling of flg22.[17] HAK5 function when potassium levels are low.[17] Flg22 has been shown to depolarize the cell’s plasma membrane with HAK5 and ILK1 working together to mediate ion homeostasis to assist with both short and long term actions such as growth and suppression thereof.[17]

References

  1. ↑ 1.0 1.1 1.2 Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S (1996). "Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase". Nature. 379 (6560): 91–6. doi:10.1038/379091a0. PMID 8538749.
  2. ↑ 2.0 2.1 Dedhar S, Williams B, Hannigan G (1999). "Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling". Trends in Cell Biology. 9 (8): 319–23. doi:10.1016/s0962-8924(99)01612-8. PMID 10407411.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Widmaier M, Rognoni E, Radovanac K, Azimifar SB, Fässler R (2012). "Integrin-linked kinase at a glance". Journal of Cell Science. 125 (Pt 8): 1839–43. doi:10.1242/jcs.093864. PMID 22637643.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Popescu SC, Brauer EK, Dimlioglu G, Popescu GV (2017). "Insights into the Structure, Function, and Ion-Mediated Signaling Pathways Transduced by Plant Integrin-Linked Kinases". Frontiers in Plant Science. 8: 376. doi:10.3389/fpls.2017.00376. PMID 28421082.
  5. ↑ "Entrez Gene: ILK integrin-linked kinase".
  6. ↑ Lange A, Wickström SA, Jakobson M, Zent R, Sainio K, Fässler R (October 2009). "Integrin-linked kinase is an adaptor with essential functions during mouse development". Nature. 461 (7266): 1002–6. doi:10.1038/nature08468. PMID 19829382.
  7. ↑ Fukuda K, Gupta S, Chen K, Wu C, Qin J (December 2009). "The pseudoactive site of ILK is essential for its binding to alpha-Parvin and localization to focal adhesions". Molecular Cell. 36 (5): 819–30. doi:10.1016/j.molcel.2009.11.028. PMC 2796127. PMID 20005845.
  8. ↑ Qin J, Wu C (October 2012). "ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling". Current Opinion in Cell Biology. 24 (5): 607–13. doi:10.1016/j.ceb.2012.06.003. PMC 3467332. PMID 22763012.
  9. ↑ Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S (February 2008). "Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization". The Journal of Cell Biology. 180 (4): 681–9. doi:10.1083/jcb.200710074. PMC 2265580. PMID 18283114.
  10. ↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
  11. ↑ Barry FA, Gibbins JM (April 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". The Journal of Biological Chemistry. 277 (15): 12874–8. doi:10.1074/jbc.M200482200. PMID 11825911.
  12. ↑ Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (September 1998). "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proceedings of the National Academy of Sciences of the United States of America. 95 (19): 11211–6. doi:10.1073/pnas.95.19.11211. PMC 21621. PMID 9736715.
  13. ↑ Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S (July 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". The Journal of Biological Chemistry. 276 (29): 27462–9. doi:10.1074/jbc.M102940200. PMID 11313365.
  14. ↑ Leung-Hagesteijn C, Mahendra A, Naruszewicz I, Hannigan GE (May 2001). "Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1". The EMBO Journal. 20 (9): 2160–70. doi:10.1093/emboj/20.9.2160. PMC 125446. PMID 11331582.
  15. ↑ Tu Y, Li F, Goicoechea S, Wu C (March 1999). "The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells". Molecular and Cellular Biology. 19 (3): 2425–34. doi:10.1128/mcb.19.3.2425. PMC 84035. PMID 10022929.
  16. ↑ Zhang Y, Chen K, Guo L, Wu C (October 2002). "Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1-ILK interaction, cell spreading, and migration". The Journal of Biological Chemistry. 277 (41): 38328–38. doi:10.1074/jbc.M205576200. PMID 12167643.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 Brauer E (June 2016). "The Raf-like Kinsase ILK1 and the High Affinity K+ Transporter HAK5 Are Required for Innate Immunity and Abiotic Stress Response". Plant Physiology. 171: 1470–1484 – via American Society of Plant Biologists.
  18. ↑ Alemán F, Nieves-Cordones M, Martínez V, Rubio F (2011). "Root K(+) acquisition in plants: the Arabidopsis thaliana model". Plant & Cell Physiology. 52 (9): 1603–12. doi:10.1093/pcp/pcr096. PMID 21771865.
  19. ↑ Chinchilla D, Bauer Z, Regenass M, Boller T, Felix G (2006). "The Arabidopsis receptor kinase FLS2 binds flg22 and determines the specificity of flagellin perception". The Plant Cell. 18 (2): 465–76. doi:10.1105/tpc.105.036574. PMC 1356552. PMID 16377758.
  20. ↑ 20.0 20.1 Wang Y, Wu WH (October 2017). "Regulation of potassium transport and signaling in plants". Current Opinion in Plant Biology. 39: 123–128. doi:10.1016/j.pbi.2017.06.006. PMID 28710919.

Further reading

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