Signal control through Raf: in sickness and in health

Abstract

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogen-activated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus of the field. In this review, we describe new as well as old findings in the regulation of the ERK1/2 pathway in normal and disease states via MAP3Ks.

Figure 1

Activity of the ERK1/2 MAPK cascade can be modulated by inputs at different sites in the pathway. The best studied mechanism of ERK1/2 activation is through receptor tyrosine kinases. Signaling events at the plasma membrane initiate the cascade through ligand/receptor binding. The signal is transmitted by recruiting adaptor proteins (e.g., Grb2) and exchange factors (e.g., SOS) that induce the activation of Ras at the plasma membrane. The activated, GTP-bound Ras then transmits the signal by activating Raf protein kinases (MAP3Ks). Rafs activate MEK1/2 through phosphorylation, which in turn phosphorylate ERK1/2. Once activated, ERK1/2 propagate the signal by affecting a variety of downstream signaling pathways. Additional components that can provide inputs to the cascade are shown including a KSR-associated AKAP and the calcium-dependent phosphatase calcineurin.

Figure 2

Calcineurin reverses negative feedback on B-Raf to permit ERK1/2 activation by nutrients in pancreatic β cells. Once activated, ERK1/2 can phosphorylate multiple upstream components in the pathway. In β cells, in response to nutrients ERK1/2 phosphorylate B-Raf preventing its continued stimulation of MEK1/2. B-Raf is required for the activation of ERK1/2 by nutrients. The calcium-dependent phosphatase calcineurin can dephosphorylate a key inhibitory site on B-Raf, allowing continued ERK1/2 activation.

Figure 3

RSPH3 3 is a mammalian AKAP that binds ERK1/2. RSPH3 is the human homolog of a protein found in motile cilia that forms part of radial spokes that connect the inner to the outer pairs of microtubules. RSPH3 is also an AKAP. ERK1/2 bind directly to RSPH3 and phosphorylate it, altering its interactions with the regulatory subunit of PKA.