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FERMT3

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Protein-coding gene in the species Homo sapiens

FERMT3
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

2YS3

Identifiers
AliasesFERMT3, KIND3, MIG-2, MIG2B, UNC112C, URP2, URP2SF, fermitin family member 3, FERM domain containing kindlin 3
External IDsOMIM: 607901; MGI: 2147790; HomoloGene: 12877; GeneCards: FERMT3; OMA:FERMT3 - orthologs
Gene location (Human)
Chromosome 11 (human)
Chr.Chromosome 11 (human)
Chromosome 11 (human)Genomic location for FERMT3Genomic location for FERMT3
Band11q13.1Start64,206,678 bp
End64,223,891 bp
Gene location (Mouse)
Chromosome 19 (mouse)
Chr.Chromosome 19 (mouse)
Chromosome 19 (mouse)Genomic location for FERMT3Genomic location for FERMT3
Band19|19 AStart6,976,326 bp
End6,996,837 bp
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • granulocyte

  • monocyte

  • spleen

  • bone marrow cells

  • appendix

  • blood

  • lymph node

  • upper lobe of left lung

  • right lung

  • thymus
Top expressed in
  • stroma of bone marrow

  • tibiofemoral joint

  • blood

  • spleen

  • granulocyte

  • mesenteric lymph nodes

  • body of femur

  • fetal liver hematopoietic progenitor cell

  • thymus

  • internal carotid artery
More reference expression data
BioGPS
n/a
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
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 MbChr 19: 6.98 – 7 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

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. 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

FERMT-3 protein sequence

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. 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.

Function

FERMT 3 Structure

The FERMT3 protein has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Kindlin 3 is a cytoskeletal signalling protein involved in the activation of the glycoprotein receptor, integrin. Together with the Talin protein it binds cooperatively to beta integrin's cytoplasmic domain causing tail reorientation, thus altering the molecule's conformation. 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. FERMT3 functions as a stabilizer of the cytoskeleton and regulates its dynamics in cell and organelle motility.

Clinical significance

FERMT3 mutations can result in autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). a deficiency in beta1, beta2 and beta3 integrin activation in platelets and leukocytes that causes haemorrhaging and recurrent infections. 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. 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.

FERMT3 deficiency on β(2) integrin function depend on both cell type (Natural killer cell or Leukocytes) and the integrin activation stimulus. 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. Leukocyte adhesion deficiency is diagnosed clinically and by complete blood counts that reveal leukocytosis with neutrophilia. 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.

References

  1. ^ GRCh38: Ensembl release 89: ENSG00000149781Ensembl, May 2017
  2. ^ GRCm38: Ensembl release 89: ENSMUSG00000024965Ensembl, 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. S2CID 32140559.
  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. Bibcode:2014MolPE..80..193A. 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. S2CID 57373556.
  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. S2CID 24844044.
  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. S2CID 7904715.

Further reading

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

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