ARAF

Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene.[5] A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.[6]

ARAF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1WXM, 2MSE
Identifiers
Aliases	ARAF, A-Raf proto-oncogene, serine/threonine kinase, A-RAF, ARAF1, PKS2, RAFA1, Serine/threonine-protein kinase A-Raf
External IDs	OMIM: 311010 MGI: 88065 HomoloGene: 1249 GeneCards: ARAF
Gene location (Human) Chr. X chromosome (human)[1] Band Xp11.3 Start 47,561,205 bp[1] End 47,571,908 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X A1.3|X 16.3 cM Start 20,664,053 bp[2] End 20,726,758 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle body of stomach body of pancreas right lobe of liver gastric mucosa transverse colon left uterine tube right lobe of thyroid gland left coronary artery upper lobe of left lung Top expressed in dorsomedial hypothalamic nucleus lateral hypothalamus mammillary body ventral tegmental area paraventricular nucleus of hypothalamus ventromedial nucleus arcuate nucleus habenula median eminence dorsal tegmental nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding metal ion binding kinase activity protein serine/threonine kinase activity protein binding ATP binding MAP kinase kinase kinase activity mitogen-activated protein kinase kinase binding Cellular component mitochondrion cytosol cellular component Biological process intracellular signal transduction regulation of TOR signaling phosphorylation negative regulation of apoptotic process positive regulation of peptidyl-serine phosphorylation MAPK cascade protein phosphorylation regulation of proteasomal ubiquitin-dependent protein catabolic process signal transduction multicellular organism development negative regulation of signal transduction cell differentiation positive regulation of ERK1 and ERK2 cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr X: 20.66 – 20.73 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Compared to the other members of this family (Raf-1 and B-Raf), very little is known about A-Raf. It seems to share many of the properties of the other isoforms, but its biological functions are not as thoroughly researched. All three Raf proteins are involved in the MAPK signaling pathway.

There are several ways A-Raf is different from the other Raf kinases. A-Raf is the only steroid hormone-regulated Raf isoform.[7] In addition, the A-Raf protein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region). This could be responsible for its low basal activity.[8]

Like Raf-1 and B-Raf, A-Raf activates MEK proteins which causes the activation of ERK and ultimately leads to cell cycle progression and cell proliferation. All three Raf proteins are located in the cytosol in their inactive state when bound to 14-3-3. In the presence of active Ras, they translocate to the plasma membrane.[9] Among the Ras kinase family, A-Raf has the lowest kinase activity towards MEK proteins in the Raf kinase family.[10] Thus, it is possible that A-Raf has other functions outside the MAPK pathway or that it helps the other Raf kinases activate the MAPK pathway. In addition to phosphorylating MEK, A-Raf also inhibits MST2, a tumor suppressor and proapoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A-Raf can prevent apoptosis from occurring. However, this inhibition is only possible when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-Raf protein. Tumorous cells often overexpress hnRNP H. When hnRNP H is downregulated, the A-RAF gene is alternatively spliced. This prevents the expression of full-length A-Raf protein.[11] Thus, overexpression of hnRNP H in tumor cells leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive.

A-Raf also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells.[12] A-Raf upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. In cancer cells, the ratio between dimeric and tetrameric forms of PKM2 determines what happens to glucose carbons. If PKM2 is in the dimeric form, glucose is channeled into synthetic processes such as nucleic acid, amino acid, or phospholipid synthesis. If A-Raf is present, PKM2 is more likely to be in the tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell. Thus, A-Raf can be linked to energy metabolism regulation and cell transformation, both of which are very important in tumorigenesis.[13]

In addition, researchers have proposed a model of how A-Raf is linked to endocytosis. Upstream of A-Raf, receptor tyrosine kinases (RTKs) are activated, leading to RAS-mediated activation of Raf kinases, including A-Raf. Once activated, A-Raf binds to membranes rich in Phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5)P₂ and signals endosomes. This leads to activation of ARF6, a central regulator of endocytic trafficking.[14]