Review articleRole of Raf Proteins in Cardiac Hypertrophy and Cardiomyocyte Survival
Section snippets
Activation of Raf Family Members
Activation of Raf-1 is a complex multistep process (Wellbrock et al. 2004). In general, GTP loading of the ras GTPase is required to initiate Raf-1 activation (Figure 1). Ras activation can occur in response to growth factor receptor-mediated relocation of protein complexes that include guanine nucleotide exchange factors, such as a protein called Son of sevenless (SOS), to the plasma membrane of cells where ras is constitutively located (Nimnual and Bar-Sagi 2002). SOS-mediated GTP loading
The ERK Cascade
Three- and four-component intracellular protein kinase cascades are thought to exist as a mechanism for massive signal amplification in response to an initiating stimulus. The best-described three-component kinase cascade is the ERK pathway that includes the initiating kinase Raf-1, B-Raf, or A-Raf, the middle kinase mitogen-activated protein kinase kinase (MKK) 1 or MKK2 (hereafter referred to as MKK), and the terminal kinase ERK1 or ERK2 (hereafter referred to as ERK) (Guan 1994, Seger and
MKK-Independent Functions of Raf Proteins
Although the role of Raf kinases in the ras–Raf–MKK–ERK cascade is well established, additional MKK- and ERK-independent functions of Raf kinases may exist. For example, mice deficient in Raf-1 exhibit normal ERK activation in many tissues but do not survive embryonic development and die by embryonic day 16.5 (Mikula et al. 2001). Raf-1−/− embryos display growth retardation with vascular defects in the yolk sac and placenta (Huser et al., 2001, Mikula et al. 2001). In addition, Raf-1−/− embryos
Analysis of Raf Function in Cultured Cardiomyocytes and in Rodent Model Systems
A large number of investigators previously examined the role of Raf-1, MKK, and ERK in the growth of neonatal rat cardiomyocytes in culture. Various studies relied on the expression of dominant negative forms of these signaling proteins or on the use of chemical inhibitors of various components of this cascade. Many—but not all—of these studies support the model that Raf, MKK, and ERK activation are required for the ligand-induced growth of cardiomyocytes (Bueno and Molkentin 2002). In
Conclusion
Recent studies with genetically modified mice have investigated the role of Raf proteins in cardiomyocyte growth and survival (Harris et al. 2004, Yamaguchi et al. 2004). One conclusion that emerges from these studies is that Raf-1 has potent antiapoptotic activity in cardiomyocytes that is independent of MKK and ERK activation and that may be dependent on its ability to block ASK1 (Figure 2). It is important to note that MKK and ERK also have antiapoptotic activity in cardiomyocytes that is
References (41)
- et al.
Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy
J Mol Cell Cardiol
(2000) - et al.
Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine 338
Curr Biol
(2000) The mitogen activated protein kinase signal transduction pathway: From the cell surface to the nucleus
Cell Signal
(1994)- et al.
Isotype-specific functions of Raf kinases
Exp Cell Res
(1999) - et al.
Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine
Cell
(1996) - et al.
Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites
Curr Biol
(2003) - et al.
Negative regulation of Raf activity by binding of 14-3-3 to the amino terminus of Raf in vivo
Mech Dev
(1997) - et al.
Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy
J Mol Cell Cardiol
(2000) - et al.
Mammalian Ras interacts directly with the serine/threonine kinase Raf
Cell
(1993) - et al.
Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes
J Biol Chem
(2001)