FERMT3

Fermitin family homolog 3) (FERMT3), also known as kindlin-3 (KIND3), MIG2-like protein (MIG2B), or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene.[5][6][7] The kindlin family of proteins, member of the B4.1 superfamily, comprises three conserved protein homologues, kindlin 1, 2, and 3. They each contain a bipartite FERM domain comprising four subdomains F0, F1, F2, and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome, leukocyte adhesion deficiency, cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore, they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis[8]

FERMT-3 protein sequence

FERMT3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2YS3
Identifiers
Aliases	FERMT3, KIND3, MIG-2, MIG2B, UNC112C, URP2, URP2SF, fermitin family member 3
External IDs	OMIM: 607901 MGI: 2147790 HomoloGene: 12877 GeneCards: FERMT3
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.1 Start 64,206,678 bp[1] End 64,223,886 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 A Start 6,998,958 bp[2] End 7,019,469 bp[2]
Gene ontology Molecular function • integrin binding Cellular component • podosome • cell junction • cell projection • extracellular exosome • membrane • extracellular region • platelet alpha granule lumen Biological process • leukocyte cell-cell adhesion • integrin-mediated signaling pathway • regulation of cell-cell adhesion mediated by integrin • integrin activation • substrate adhesion-dependent cell spreading • cell adhesion • platelet aggregation • positive regulation of cell migration • platelet degranulation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	83706	108101
Ensembl	ENSG00000149781	ENSMUSG00000024965
UniProt	Q86UX7	Q8K1B8
RefSeq (mRNA)	NM_031471 NM_178443 NM_001382361 NM_001382362 NM_001382363 NM_001382364 NM_001382448	NM_153795 NM_001362399
RefSeq (protein)	NP_113659 NP_848537 NP_001369290 NP_001369291 NP_001369292 NP_001369293 NP_001369377	NP_722490 NP_001349328
Location (UCSC)	Chr 11: 64.21 – 64.22 Mb	Chr 19: 7 – 7.02 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Evolution

It has been suggested that the evolutionary source of a single ancestral Kindlin protein is the earliest metazoa, the Parazoa. Within vertebrates, these ancestral proteins were subjected to duplication processes in order to arrive at the actual Kindlin family. In comparison with other members of the B4.1 superfamily of proteins, the FERM domains in Kindlin homologues have a greater degree of conservation.[9] The presence of an inserted pleckstrin homology domain within the FERM domain, suggests that the metazoan evolution of the FERM domain is the origination from a proto-talin protein in unicellular or proto-multicellular organisms.[9][10]

Function

FERMT 3 Structure

The FERMT3 protein has a key role in the regulation of hemostasis and thrombosis.[10] This protein may also help maintain the membrane skeleton of erythrocytes.[5] Kindlin 3 is a cytoskeletal signalling protein involved in the activation of the glycoprotein receptor, integrin.[11] Together with the Talin protein it binds cooperatively to beta integrin’s cytoplasmic domain causing tail reorientation, thus altering the molecule’s conformation.[12] Modification of integrin’s conformation serves to dissociate alpha and beta subunits by disrupting their interactions and helping the molecule adopt a high affinity state.[9] FERMT3 functions as a stabilizer of the cytoskeleton and regulates its dynamics in cell and organelle motility.[13]

Clinical significance

FERMT3 mutations can result in autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III).[5] a deficiency in beta1, beta2 and beta3 integrin activation in platelets and leukocytes that causes haemorrhaging and recurrent infections.[10] Loss of FERMT3 expression in leukocytes compromises their adhesion to the inflamed endothelia and affects neutrophil binding and spreading while selectin mediated rolling is unaffected.[14] It has also been found that FERMT3 lowers Natural Killer cell’s activation threshold, such that a loss of FERMT3 affects single receptor activation of NK cell-mediated cytotoxicity but has no impact on multiple receptors, where the protein deficiency is overcome and target cells are killed.[15]

FERMT3 deficiency on β(2) integrin function depend on both cell type (Natural killer cell or Leukocytes) and the integrin activation stimulus.[16] The prevention of the beta-3 activation is specifically related to LAD-3, causing Glanzmann's thrombasthenia symptoms, a condition in which patients bleed excessively.[17] Leukocyte adhesion deficiency is diagnosed clinically and by complete blood counts that reveal leukocytosis with neutrophilia.[16] Management and treatment of this disease aim to control these recurrent infections by antibiotics and blood transfusions, with bone marrow transplantation as the only curative measure. Failure to express the FERMT3 protein disrupts the ability to form clots and coagulate by preventing integrin αIIβ3-mediated platelet aggregation.[10]

References

1. GRCh38: Ensembl release 89: ENSG00000149781 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024965 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: fermitin family homolog 3 (Drosophila)".
6. Weinstein EJ, Bourner M, Head R, Zakeri H, Bauer C, Mazzarella R (April 2003). "URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1637 (3): 207–16. doi:10.1016/S0925-4439(03)00035-8. PMID 12697302.
7. Boyd RS, Adam PJ, Patel S, Loader JA, Berry J, Redpath NT, Poyser HR, Fletcher GC, Burgess NA, Stamps AC, Hudson L, Smith P, Griffiths M, Willis TG, Karran EL, Oscier DG, Catovsky D, Terrett JA, Dyer MJ (August 2003). "Proteomic analysis of the cell-surface membrane in chronic lymphocytic leukemia: identification of two novel proteins, BCNP1 and MIG2B". Leukemia. 17 (8): 1605–12. doi:10.1038/sj.leu.2402993. PMID 12886250.
8. Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV (March 2009). "A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans". Nature Medicine. 15 (3): 313–8. doi:10.1038/nm.1917. PMC 2857384. PMID 19234460.
9. Ali RH, Khan AA (November 2014). "Tracing the evolution of FERM domain of Kindlins". Molecular Phylogenetics and Evolution. 80: 193–204. doi:10.1016/j.ympev.2014.08.008. PMID 25150025.
10. Lai-Cheong JE, Parsons M, McGrath JA (May 2010). "The role of kindlins in cell biology and relevance to human disease". The International Journal of Biochemistry & Cell Biology. 42 (5): 595–603. doi:10.1016/j.biocel.2009.10.015. PMID 19854292.
11. Danen EHJ (2000–13). Integrins: An Overview of Structural and Functional Aspects. Madame Curie Bioscience Database. Landes Bioscience.
12. Rognoni E, Ruppert R, Fässler R (January 2016). "The kindlin family: functions, signaling properties and implications for human disease". Journal of Cell Science. 129 (1): 17–27. doi:10.1242/jcs.161190. PMID 26729028.
13. Sun Z, Costell M, Fässler R (January 2019). "Integrin activation by talin, kindlin and mechanical forces". Nature Cell Biology. 21 (1): 25–31. doi:10.1038/s41556-018-0234-9. PMID 30602766.
14. Stadtmann A, Zarbock A (January 2017). "The role of kindlin in neutrophil recruitment to inflammatory sites". Current Opinion in Hematology. 24 (1): 38–45. doi:10.1097/MOH.0000000000000294. PMID 27749372.
15. Fagerholm SC, Lek HS, Morrison VL (2014). "Kindlin-3 in the immune system". American Journal of Clinical and Experimental Immunology. 3 (1): 37–42. PMC 3960760. PMID 24660120.
16. Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N (March 2009). "Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation". Nature Medicine. 15 (3): 306–12. doi:10.1038/nm.1931. PMC 2680140. PMID 19234463.
17. Karaköse E, Schiller HB, Fässler R (July 2010). "The kindlins at a glance". Journal of Cell Science. 123 (Pt 14): 2353–6. doi:10.1242/jcs.064600. PMID 20592181.

Further reading

• Etzioni A (October 2009). "Genetic etiologies of leukocyte adhesion defects". Current Opinion in Immunology. 21 (5): 481–6. doi:10.1016/j.coi.2009.07.005. PMID 19647987.
• Mory A, Feigelson SW, Yarali N, Kilic SS, Bayhan GI, Gershoni-Baruch R, Etzioni A, Alon R (September 2008). "Kindlin-3: a new gene involved in the pathogenesis of LAD-III". Blood. 112 (6): 2591. doi:10.1182/blood-2008-06-163162. PMID 18779414.</ref>
• Lehner B, Sanderson CM (July 2004). "A protein interaction framework for human mRNA degradation". Genome Research. 14 (7): 1315–23. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
• Bialkowska K, Ma YQ, Bledzka K, Sossey-Alaoui K, Izem L, Zhang X, Malinin N, Qin J, Byzova T, Plow EF (June 2010). "The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell". The Journal of Biological Chemistry. 285 (24): 18640–9. doi:10.1074/jbc.M109.085746. PMC 2881789. PMID 20378539.
• McDowall A, Svensson L, Stanley P, Patzak I, Chakravarty P, Howarth K, Sabnis H, Briones M, Hogg N (June 2010). "Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro". Blood. 115 (23): 4834–42. doi:10.1182/blood-2009-08-238709. PMID 20357244.
• Harburger DS, Bouaouina M, Calderwood DA (April 2009). "Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects". The Journal of Biological Chemistry. 284 (17): 11485–97. doi:10.1074/jbc.M809233200. PMC 2670154. PMID 19240021.
• Manevich-Mendelson E, Feigelson SW, Pasvolsky R, Aker M, Grabovsky V, Shulman Z, Kilic SS, Rosenthal-Allieri MA, Ben-Dor S, Mory A, Bernard A, Moser M, Etzioni A, Alon R (September 2009). "Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions". Blood. 114 (11): 2344–53. doi:10.1182/blood-2009-04-218636. PMID 19617577.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.