FASTKD1

FAST kinase domain-containing protein 1 is a protein that in humans is encoded by the FASTKD1 gene on chromosome 2.[5][6] This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress.[7] FASTKD1 is also an RNA-binding protein and has been associated with endometrial cancer.[8][9]

FASTKD1
Identifiers
AliasesFASTKD1, FAST kinase domains 1
External IDsOMIM: 617529 MGI: 2444596 HomoloGene: 36420 GeneCards: FASTKD1
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2q31.1Start169,528,508 bp[1]
End169,573,875 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

79675

320720

Ensembl

ENSG00000138399

ENSMUSG00000027086

UniProt

Q53R41

Q6DI86

RefSeq (mRNA)

NM_001281476
NM_024622
NM_001322046
NM_001322048
NM_001322049

NM_177244

RefSeq (protein)

NP_001268405
NP_001308975
NP_001308977
NP_001308978
NP_078898

NP_796218

Location (UCSC)Chr 2: 169.53 – 169.57 MbChr 2: 69.69 – 69.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

FASTKD1 shares structural characteristics of the FASTKD family, including an N-terminal mitochondrial targeting domain and three C-terminal domains: two FAST kinase-like domains (FAST_1 and FAST_2) and a RNA-binding domain (RAP).[7][10] The mitochondrial targeting domain directs FASTKD1 to be imported into the mitochondria. Though the functions of the C-terminal domains are unknown, RAP possibly binds RNA during trans-splicing.[7]

Function

As a member of the FASTKD family, FASTKD1 localizes to the mitochondria to modulate their energy balance, especially under conditions of stress. Though ubiquitously expressed in all tissues, FASTKD1 appears more abundantly in skeletal muscle, heart muscle, and other tissues enriched in mitochondria.[7] FASTKD1 has been validated as an RNA-binding protein.[8][11]

Clinical Significance

FASTKD1 is an important apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[12] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.

FASTKD1 has been identified as a potential molecular biomarker for endometrial cancer, a cancer of the female genital tract, most notably using uterine aspirates[9] This finding represent the basis for the development of a highly sensitive and specific minimally invasive method for the screenings of endometrial cancer. Accordingly, gene expression screening on 52 carcinoma samples and series of real-time quantitative PCR validation on 19 paired carcinomas and normal tissue samples and on 50 carcinoma and non carcinoma uterine aspirates were performed to identify and validate potential biomarkers of endometrial cancer.[9] Furthermore, another study designed a strategy to explore gene expression signatures associated with the survival in acute lymphoblastic leukemia (ALL), to search for aberrant gene activity, which consists of applying several filters to transcriptomic datasets from two pediatric ALL studies. Six genes whose expression in leukemic blasts was associated with prognosis were identified:three genes predicting poor prognosis (AK022211, FASTKD1 and STARD4) and three genes associated with a favorable outcome (CAMSAP1, PCGF6 and SH3RF3). Thus it appears that FASTKD1 may also play a role in ALL.[13]

References
  1. GRCh38: Ensembl release 89: ENSG00000138399 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000027086 - 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. "FAST kinase domains 1".
  6. "Entrez Gene: FAST kinase domains 1".
  7. Simarro M, Gimenez-Cassina A, Kedersha N, Lazaro JB, Adelmant GO, Marto JA, Rhee K, Tisdale S, Danial N, Benarafa C, Orduña A, Anderson P (Oct 2010). "Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration". Biochemical and Biophysical Research Communications. 401 (3): 440–6. doi:10.1016/j.bbrc.2010.09.075. PMC 2963690. PMID 20869947.
  8. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM, Krijgsveld J, Hentze MW (Jun 2012). "Insights into RNA biology from an atlas of mammalian mRNA-binding proteins". Cell. 149 (6): 1393–406. doi:10.1016/j.cell.2012.04.031. PMID 22658674.
  9. Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, Rigau M, Garcia M, Ertekin T, Montes M, Lopez-Lopez R, Carreras R, Xercavins J, Ortega A, Maes T, Rosell E, Doll A, Abal M, Reventos J, Gil-Moreno A (Nov 2011). "Molecular markers of endometrial carcinoma detected in uterine aspirates". International Journal of Cancer. 129 (10): 2435–44. doi:10.1002/ijc.25901. PMID 21207424. S2CID 11956280.
  10. Yeung KT, Das S, Zhang J, Lomniczi A, Ojeda SR, Xu CF, Neubert TA, Samuels HH (Jun 2011). "A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2". Molecular and Cellular Biology. 31 (11): 2287–98. doi:10.1128/MCB.01381-10. PMC 3133243. PMID 21444724.
  11. Baltz AG, Munschauer M, Schwanhäusser B, Vasile A, Murakawa Y, Schueler M, Youngs N, Penfold-Brown D, Drew K, Milek M, Wyler E, Bonneau R, Selbach M, Dieterich C, Landthaler M (Jun 2012). "The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts". Molecular Cell. 46 (5): 674–90. doi:10.1016/j.molcel.2012.05.021. PMID 22681889.
  12. Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.
  13. Wang J, Mi JQ, Debernardi A, Vitte AL, Emadali A, Meyer JA, Charmpi K, Ycart B, Callanan MB, Carroll WL, Khochbin S, Rousseaux S (Jun 2015). "A six gene expression signature defines aggressive subtypes and predicts outcome in childhood and adult acute lymphoblastic leukemia". Oncotarget. 6 (18): 16527–42. doi:10.18632/oncotarget.4113. PMC 4599287. PMID 26001296.
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