FASTKD2

Last updated
FASTKD2
Identifiers
Aliases FASTKD2 , KIAA0971, FAST kinase domains 2, COXPD44
External IDs OMIM: 612322 MGI: 1922869 HomoloGene: 8957 GeneCards: FASTKD2
Orthologs
SpeciesHumanMouse
Entrez

22868

75619

Ensembl

ENSG00000118246

ENSMUSG00000025962

UniProt

Q9NYY8

Q922E6

RefSeq (mRNA)

NM_014929
NM_001136193
NM_001136194

NM_172422

RefSeq (protein)

NP_001129665
NP_001129666
NP_055744

NP_766010

Location (UCSC) Chr 2: 206.77 – 206.8 Mb Chr 1: 63.77 – 63.79 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

FAST kinase domain-containing protein 2 (FASTKD2) is a protein that in humans is encoded by the FASTKD2 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. FASTKD2 has been implicated in mitochondrial encephalomyopathy, breast cancer, and prostate cancer. [7] [8] [9]

Contents

Structure

FASTKD2 shares structural characteristics of the FASTKD family, including a ~50-amino acid 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] [8] The mitochondrial targeting domain directs FASTKD2 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, FASTKD2 localizes to the inner mitochondrial membrane to modulate their energy balance, especially under conditions of stress. [7] [8] Though ubiquitously expressed in all tissues, FASTKD2 appears more abundantly in skeletal muscle, heart muscle, and other tissues enriched in mitochondria. [7] Nonetheless, FASTKD2 has been observed to mediate apoptosis independent of import into the mitochondria, suggesting that it interacts with proteins on the outer mitochondrial membrane. This protein possibly contributes its proapoptotic function through a caspase-dependent pathway, by activating proapoptotic factors or inhibiting antiapoptotic factors, but the exact mechanism remain unclear. [8] [9] FASTKD2 has also been validated as an RNA-binding protein. [10] [11]

Clinical significance

FASTKD2 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.

FASTKD2 has been linked to mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency (mitochondrial complex IV deficiency). Nonsense mutations in FASTKD2 produce a truncated protein that cuts off the RAP domain and part of the FAST domains, leading to dampened sensitivity to apoptotic stimuli. [7] [10] Moreover, breast cancer cells are protected against apoptosis by stimulating NRIF3/DD1 expression or DIF-1 knockdown, which thus suppresses the proapoptotic function of FASTKD2. [8] The proapoptotic function is similarly observed in prostate cancer cells, but not in other cells; it is suggested that susceptibility to FASTKD2-mediated apoptosis requires certain factors to associate with the DIF-1 complex to bind. [9] Thus far, activating and enhancing expression of FASTKD2 may prove effective in killing breast and prostate cancer cells. [8] [9]

Interactions

FASTKD2 has been shown to interact with FASTKD3. [7] The FASTKD2 gene has been observed to bind the DIF-1 complex. [8]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate lost is 20 to 30 billion cells.

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. It was the first apoptosis regulator identified in any organism.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Peptidylprolyl isomerase A</span> Protein-coding gene in the species Homo sapiens

Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the PPIA gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate many biological processes, including intracellular signaling, transcription, inflammation, and apoptosis. Due to its various functions, PPIA has been implicated in a broad range of inflammatory diseases, including atherosclerosis and arthritis, and viral infections.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">DAP3</span> Protein-coding gene in the species Homo sapiens

28S ribosomal protein S29, mitochondrial, also known as death-associated protein 3 (DAP3), is a protein that in humans is encoded by the DAP3 gene on chromosome 1. This gene encodes a 28S subunit protein of the mitochondrial ribosome (mitoribosome) and plays key roles in translation, cellular respiration, and apoptosis. Moreover, DAP3 is associated with cancer development, but has been observed to aid some cancers while suppressing others.

<span class="mw-page-title-main">SIVA1</span> Protein-coding gene in the species Homo sapiens

Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene. This gene encodes a protein with an important role in the apoptotic pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.

<span class="mw-page-title-main">TBRG4</span> Protein-coding gene in the species Homo sapiens

Transforming growth factor beta regulator 4 (TBRG4), also known as cell cycle progression restoration protein 2 (CPR2) and FAST kinase domain-containing protein 4 (FASTKD4), is a protein that in humans is encoded by the TBRG4 gene on chromosome 7. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress and cell cycle progression. TBRG4 is involved in cell proliferation in hematopoiesis and multiple myeloma.

<span class="mw-page-title-main">ENDOG</span> Protein-coding gene in the species Homo sapiens

Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson’s disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.

<span class="mw-page-title-main">AIFM2</span> Protein-coding gene in the species Homo sapiens

Apoptosis-inducing factor 2 (AIFM2), also known as ferroptosis suppressor protein 1 (FSP1), apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.

<span class="mw-page-title-main">PLSCR3</span> Protein-coding gene in the species Homo sapiens

Phospholipid scramblase 3 is an enzyme that in humans is encoded by the PLSCR3 gene. Like the other phospholipid scramblase family members, PLS3 is a type II plasma membrane protein that is rich in proline and integral in apoptosis, or programmed cell death. The regulation of apoptosis is critical for both cell development and tissue homeostasis

<span class="mw-page-title-main">HK2</span>

Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009]

<span class="mw-page-title-main">FASTKD3</span> Protein-coding gene in the species Homo sapiens

FAST kinase domain-containing protein 3 (FASTKD3) is a protein that in humans is encoded by the FASTKD3 gene on chromosome 5. This protein is part of the Fas-activated serine/threonine kinase domain (FASTKD) containing protein family, which is known for regulating the energy balance of mitochondria under stress.

<span class="mw-page-title-main">ADP/ATP translocase 2</span> Protein-coding gene in humans

ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.

<span class="mw-page-title-main">MUL1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is an enzyme that in humans is encoded by the MUL1 gene on chromosome 1. This enzyme localizes to the outer mitochondrial membrane, where it regulates mitochondrial morphology and apoptosis through multiple pathways, including the Akt, JNK, and NF-κB. Its proapoptotic function thus implicates it in cancer and Parkinson’s disease.

<span class="mw-page-title-main">FASTKD1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">FASTKD5</span> Protein-coding gene in the species Homo sapiens

FAST kinase domain-containing protein 5 (FASTKD5) is a protein that in humans is encoded by the FASTKD5 gene on chromosome 20. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress. FASTKD5 is also required for RNA granules to process precursor mRNAs not flanked by tRNAs.

<span class="mw-page-title-main">FAM162A</span> Protein-coding gene in the species Homo sapiens

Human growth and transformation-dependent protein (HGTD-P), also called E2-induced gene 5 protein (E2IG5), is a protein that in humans is encoded by the FAM162A gene on chromosome 3. This protein promotes intrinsic apoptosis in response to hypoxia via interactions with hypoxia-inducible factor-1α (HIF-1α). As a result, it has been associated with cerebral ischemia, myocardial infarction, and various cancers.

<span class="mw-page-title-main">RMDN3</span> Protein-coding gene in the species Homo sapiens

Regulator of microtubule dynamics protein 3 (RMDN3), more commonly known as Protein tyrosine phosphatase interacting protein 51 (PTPIP51), is a protein that in humans is encoded by the RMDN3 gene on chromosome 15. This protein contributes to multiple biological functions, including cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis, and has been associated with numerous cancers.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000118246 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025962 - 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. ↑ UniProt: Q9NYY8
  6. ↑ "Entrez Gene: FAST kinase domains 2".
  7. 1 2 3 4 5 6 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 (October 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. 1 2 3 4 5 6 7 Yeung KT, Das S, Zhang J, Lomniczi A, Ojeda SR, Xu CF, Neubert TA, Samuels HH (June 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.
  9. 1 2 3 4 Das S, Yeung KT, Mahajan MA, Samuels HH (November 2014). "Fas Activated Serine-Threonine Kinase Domains 2 (FASTKD2) mediates apoptosis of breast and prostate cancer cells through its novel FAST2 domain". BMC Cancer. 14: 852. doi: 10.1186/1471-2407-14-852 . PMC   4256816 . PMID   25409762.
  10. 1 2 Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM, Krijgsveld J, Hentze MW (June 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.
  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 (June 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 (August 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.
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