Overview
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.
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. 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.
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. Among the Ras kinase family, A-Raf has the lowest kinase activity towards MEK proteins in the Raf kinase family. 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. 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.
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