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ARAF

From Wikipedia, the free encyclopedia
For other uses, see Araf (disambiguation).

ARAF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesARAF, A-Raf proto-oncogene, serine/threonine kinase, A-RAF, ARAF1, PKS2, RAFA1, Serine/threonine-protein kinase A-Raf
External IDsOMIM: 311010; MGI: 88065; HomoloGene: 1249; GeneCards: ARAF; OMA:ARAF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

369

11836

Ensembl

ENSG00000078061

ENSMUSG00000001127

UniProt

P10398
Q96II5

P04627

RefSeq (mRNA)

NM_001256196
NM_001256197
NM_001654

NM_001159645
NM_009703

RefSeq (protein)

NP_001243125
NP_001243126
NP_001645
NP_001243125.1

NP_001153117
NP_033833

Location (UCSC)Chr X: 47.56 – 47.57 MbChr X: 20.66 – 20.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Serine/threonine-protein kinase A-Raf, or simply A-Raf, is an enzyme that in humans is encoded by the ARAF gene.[5] It belongs to the Raf kinase family of serine/threonine-specific protein kinases, which also includes Raf-1 and B-Raf.[6] A-Raf is involved in the MAPK/ERK pathway, where it contributes to cell signaling processes that regulate proliferation, survival, and differentiation. Compared to Raf-1 and B-Raf, A-Raf is less well studied and exhibits distinct structural and regulatory features, including low kinase activity and alternative splicing in cancer. In addition to its role in MAPK signaling, A-Raf has functions in apoptosis suppression, cancer metabolism, and endocytic trafficking.

Structure

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A-Raf, a member of the Raf kinase family, shares a conserved domain architecture with B-Raf and C-Raf, comprising three conserved regions: CR1, CR2, and CR3.

  • CR1 (Conserved Region 1): This N-terminal region contains the Ras-binding domain (RBD) and the cysteine-rich domain (CRD). The RBD facilitates interaction with activated Ras-GTP, anchoring A-Raf to the plasma membrane.[7] The CRD, characterized by its zinc-binding motif, contributes to membrane association and protein-protein interactions[8] Structural studies confirm the RBD and CRD function as a single entity during Ras binding.[9]
  • CR2 (Conserved Region 2): Positioned between CR1 and CR3, CR2 is a serine/threonine-rich regulatory segment containing phosphorylation sites (e.g., Ser259 in Raf-1) that modulate A-Raf's activity and interactions with 14-3-3 proteins.[10] This region is critical for autoinhibition and activation dynamics.[11]
  • CR3 (Conserved Region 3): The C-terminal kinase domain exhibits the bilobal architecture characteristic of protein kinases, with an ATP-binding site between the N-terminal and C-terminal lobes.[12] Structural analyses reveal similarities to tyrosine kinase-like (TKL) group members[13]

The RBD adopts a ubiquitin-like fold critical for Ras-GTP interaction.[14], while the CRD's zinc-binding motif stabilizes membrane association.[15] A-Raf's activity is regulated by phosphorylation-dependent 14-3-3 binding.[16] and isoform dimerization, which is essential for MAPK pathway activation.[17][18]

Function

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A-Raf shares the canonical role of Raf kinases in the MAPK signaling cascade. Upon activation by Ras, A-Raf translocates from the cytosol to the plasma membrane, where it phosphorylates and activates MEK proteins. This activation leads to downstream ERK signaling and promotes cell cycle progression and proliferation.[19]

Among the Raf isoforms, A-Raf exhibits the lowest kinase activity toward MEK proteins.[20] This may be due to amino acid substitutions in a negatively charged region upstream of the kinase domain (the N-region), which result in low basal activity.[21]

A-Raf is also the only Raf kinase known to be regulated by steroid hormones.[22] In its inactive form, A-Raf is bound to 14-3-3 proteins in the cytosol; activation by Ras causes its translocation to the plasma membrane.

Beyond the MAPK pathway, A-Raf has additional functions. It inhibits MST2, a proapoptotic kinase, thereby suppressing apoptosis. This inhibitory activity is dependent on the expression of full-length A-Raf protein, which is maintained by the splicing factor hnRNP H.[23]

A-Raf also regulates energy metabolism by interacting with pyruvate kinase M2 (PKM2), a key enzyme in cancer cell glycolysis. By promoting a conformational shift from the dimeric to the tetrameric form of PKM2, A-Raf enhances its enzymatic activity and shifts glucose utilization from biosynthesis toward energy production.[24]

In addition, A-Raf has been implicated in endocytic membrane trafficking. Upon activation by receptor tyrosine kinases and Ras, A-Raf localizes to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)-rich membranes and signals to endosomes, leading to activation of ARF6, a key regulator of endocytosis.[25]

Clinical significance

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A-Raf may contribute to tumorigenesis through multiple mechanisms. In cancer cells, overexpression of hnRNP H enhances the production of full-length A-Raf, which inhibits MST2 and prevents apoptosis. The downregulation of hnRNP H, in contrast, leads to alternative splicing of the ARAF gene and loss of this anti-apoptotic activity.[26]

A-Raf’s regulation of PKM2 activity further links it to cancer metabolism. By promoting glycolytic flux toward pyruvate and lactate production, A-Raf may help sustain the high energy demands of rapidly proliferating tumor cells.[27]

Because A-Raf modulates both apoptosis and metabolism—two critical hallmarks of cancer—it may represent a potential target for future cancer therapies.

Interactions

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ARAF has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000078061 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001127 – 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: ARAF V-raf murine sarcoma 3611 viral oncogene homolog".
  6. ^ Mark GE, Seeley TW, Shows TB, Mountz JD (September 1986). "Pks, a raf-related sequence in humans". Proceedings of the National Academy of Sciences of the United States of America. 83 (17): 6312–6316. Bibcode:1986PNAS...83.6312M. doi:10.1073/pnas.83.17.6312. PMC 386493. PMID 3529082.
  7. ^ Tran TH, Chan AH, Young LC, Bindu L, Neale C, Messing S, et al. (February 2021). "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation". Nature Communications. 12 (1): 1176. Bibcode:2021NatCo..12.1176T. doi:10.1038/s41467-021-21422-x. PMC 7895934. PMID 33608534.
  8. ^ Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL (August 1996). "The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8312–8317. Bibcode:1996PNAS...93.8312M. doi:10.1073/pnas.93.16.8312. PMC 38667. PMID 8710867.
  9. ^ Tran TH, Chan AH, Young LC, Bindu L, Neale C, Messing S, et al. (February 2021). "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation". Nature Communications. 12 (1): 1176. Bibcode:2021NatCo..12.1176T. doi:10.1038/s41467-021-21422-x. PMC 7895934. PMID 33608534.
  10. ^ Light Y, Paterson H, Marais R (July 2002). "14-3-3 antagonizes Ras-mediated Raf-1 recruitment to the plasma membrane to maintain signaling fidelity". Molecular and Cellular Biology. 22 (14): 4984–4996. doi:10.1128/MCB.22.14.4984-4996.2002. PMC 139778. PMID 12077328.
  11. ^ Defrise M, Kinahan PE, Townsend DW, Michel C, Sibomana M, Newport DF (April 1997). "Exact and approximate rebinning algorithms for 3-D PET data". IEEE Transactions on Medical Imaging. 16 (2): 145–158. doi:10.1109/42.563660. PMID 9101324.
  12. ^ Defrise M, Kinahan PE, Townsend DW, Michel C, Sibomana M, Newport DF (April 1997). "Exact and approximate rebinning algorithms for 3-D PET data". IEEE Transactions on Medical Imaging. 16 (2): 145–158. doi:10.1109/42.563660. PMID 9101324.
  13. ^ Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T (July 2004). "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth". Journal of Cell Science. 117 (Pt 15): 3319–3329. doi:10.1242/jcs.01183. PMID 15226403.
  14. ^ Tran TH, Chan AH, Young LC, Bindu L, Neale C, Messing S, et al. (February 2021). "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation". Nature Communications. 12 (1): 1176. Bibcode:2021NatCo..12.1176T. doi:10.1038/s41467-021-21422-x. PMC 7895934. PMID 33608534.
  15. ^ Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL (August 1996). "The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8312–8317. Bibcode:1996PNAS...93.8312M. doi:10.1073/pnas.93.16.8312. PMC 38667. PMID 8710867.
  16. ^ Light Y, Paterson H, Marais R (July 2002). "14-3-3 antagonizes Ras-mediated Raf-1 recruitment to the plasma membrane to maintain signaling fidelity". Molecular and Cellular Biology. 22 (14): 4984–4996. doi:10.1128/MCB.22.14.4984-4996.2002. PMC 139778. PMID 12077328.
  17. ^ Rimmer A (June 2018). "Overseas doctors must not be used just to fill rota gaps, says leading consultant". BMJ. 361: k2654. doi:10.1136/bmj.k2654. PMID 29907696.
  18. ^ Rushworth LK, Hindley AD, O'Neill E, Kolch W (March 2006). "Regulation and role of Raf-1/B-Raf heterodimerization". Molecular and Cellular Biology. 26 (6): 2262–2272. doi:10.1128/MCB.26.6.2262-2272.2006. PMC 1430271. PMID 16508002.
  19. ^ Mercer K, Giblett S, Oakden A, Brown J, Marais R, Pritchard C (2005-04-25). "A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression". Oncogene. 24 (33): 5207–5217. doi:10.1038/sj.onc.1208707. ISSN 0950-9232. PMID 15856007.
  20. ^ Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. (2011-03-01). "Raf Family Kinases Old Dogs Have Learned New Tricks". Genes & Cancer. 2 (3): 232–260. doi:10.1177/1947601911407323. ISSN 1947-6019. PMC 3128629. PMID 21779496.
  21. ^ Baljuls A, Mueller T, Drexler HC, Hekman M, Rapp UR (2007-09-07). "Unique N-region determines low basal activity and limited inducibility of A-RAF kinase: the role of N-region in the evolutionary divergence of RAF kinase function in vertebrates". The Journal of Biological Chemistry. 282 (36): 26575–26590. doi:10.1074/jbc.M702429200. ISSN 0021-9258. PMID 17613527.
  22. ^ Lee JE, Beck TW, Wojnowski L, Rapp UR (1996-04-18). "Regulation of A-raf expression". Oncogene. 12 (8): 1669–1677. ISSN 0950-9232. PMID 8622887.
  23. ^ Rauch J, O'Neill E, Mack B, Matthias C, Munz M, Kolch W, et al. (2010-02-15). "Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription". Cancer Research. 70 (4): 1679–1688. doi:10.1158/0008-5472.CAN-09-2740. ISSN 0008-5472. PMC 2880479. PMID 20145135.
  24. ^ Mazurek S, Drexler HC, Troppmair J, Eigenbrodt E, Rapp UR (2007-11-01). "Regulation of Pyruvate Kinase Type M2 by A-Raf: A Possible Glycolytic Stop or Go Mechanism". Anticancer Research. 27 (6B): 3963–3971. ISSN 0250-7005. PMID 18225557.
  25. ^ Nekhoroshkova E, Albert S, Becker M, Rapp UR (2009-02-27). "A-RAF Kinase Functions in ARF6 Regulated Endocytic Membrane Traffic". PLOS ONE. 4 (2): e4647. Bibcode:2009PLoSO...4.4647N. doi:10.1371/journal.pone.0004647. ISSN 1932-6203. PMC 2645234. PMID 19247477.
  26. ^ Rauch J, O'Neill E, Mack B, Matthias C, Munz M, Kolch W, et al. (2010-02-15). "Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription". Cancer Research. 70 (4): 1679–1688. doi:10.1158/0008-5472.CAN-09-2740. ISSN 0008-5472. PMC 2880479. PMID 20145135.
  27. ^ Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. (2008-03-13). "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature. 452 (7184): 230–233. Bibcode:2008Natur.452..230C. doi:10.1038/nature06734. ISSN 0028-0836. PMID 18337823. S2CID 16111842.
  28. ^ a b c d e Yuryev A, Wennogle LP (February 2003). "Novel raf kinase protein-protein interactions found by an exhaustive yeast two-hybrid analysis". Genomics. 81 (2): 112–125. doi:10.1016/S0888-7543(02)00008-3. PMID 12620389.
  29. ^ Yin XL, Chen S, Yan J, Hu Y, Gu JX (February 2002). "Identification of interaction between MEK2 and A-Raf-1". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1589 (1): 71–76. doi:10.1016/S0167-4889(01)00188-4. PMID 11909642.
  30. ^ a b c Yuryev A, Ono M, Goff SA, Macaluso F, Wennogle LP (July 2000). "Isoform-Specific Localization of A-RAF in Mitochondria". Molecular and Cellular Biology. 20 (13): 4870–4878. doi:10.1128/MCB.20.13.4870-4878.2000. PMC 85938. PMID 10848612.
  31. ^ Yin XL, Chen S, Gu JX (February 2002). "Identification of TH1 as an interaction partner of A-Raf kinase". Molecular and Cellular Biochemistry. 231 (1–2): 69–74. doi:10.1023/A:1014437024129. PMID 11952167. S2CID 19362635.

Further reading

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[edit]
  • Human ARAF genome location and ARAF gene details page in the UCSC Genome Browser.
  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Serine/threonine-protein kinase A-Raf
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