RSK Isoforms in Acute Myeloid Leukemia

Abstract

Ribosomal S6 Kinases (RSKs) are a group of serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. Four RSK isoforms are directly activated by ERK1/2 in response to extracellular stimuli including growth factors, hormones, and chemokines. RSKs phosphorylate many cytosolic and nuclear targets resulting in the regulation of diverse cellular processes such as cell proliferation, survival, and motility. In hematological malignancies such as acute myeloid leukemia (AML), RSK isoforms are highly expressed and aberrantly activated resulting in poor outcomes and resistance to chemotherapy. Therefore, understanding RSK function in leukemia could lead to promising therapeutic strategies. This review summarizes the current information on human RSK isoforms and discusses their potential roles in the pathogenesis of AML and mechanism of pharmacological inhibitors.

Keywords: AML; RSK inhibitors; RSK isoforms; cancer; hematological malignancy.

Figure 1

A schematic model for RSK activation. When RTK is stimulated by growth factor, it activates the docking proteins GRB2 and SOS. SOS triggers Ras to exchange guanosine diphosphate (GDP) to guanosine triphosphate (GTP) and then to become activated. Ras activates Raf kinases, which phosphorylate MEK1/2, ERK1/2, and RSK1-4. Then, RSKs phosphorylate various downstream substrates to mediate diverse cellular processes.

Figure 2

The domain structure of four RSK isoforms in human. RSKs exhibit two functional domains NTKD and CTKD, which are connected by a linker region. RSKs have six conserved phosphorylation sites. C-terminal tail contains an ERK1/2-docking domain called KIM motif and PDZ-binding motif.

Figure 3

A schematic model of RSK1 activating process. Extracellular signals activate ERK1/2, which phosphorylates Thr573 in CTKD. The activated CTKD autophosphorylates Ser380 at the hydrophobic motif. In addition, ERK1/2 might carry out the phosphorylation for Thr359 and Ser363. A constitutively active Ser/Thr kinase PDK1 binds at the phosphorylated Ser380 and phosphorylates Ser211 in the NTKD, which leads to the full activation of RSKs and subsequent phosphorylation of the various substrates. This is followed by the phosphorylation of Ser749 by the NTKD, decreasing the ERK1/2 affinity for RSKs in a negative feedback loop.

Figure 4

Molecular targets and cellular function of RSK isoforms. RSKs control diverse cellular processes by regulating extensive downstream targets.

Figure 5

Functional mechanisms of RSK isoforms in AML. RSKs control survival and apoptosis of leukemic cells through aberrantly activated upstream signaling.