Review article
Role of Raf Proteins in Cardiac Hypertrophy and Cardiomyocyte Survival

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Abstract

Cardiomyocyte survival and growth are regulated by the action of extracellular ligands that activate intracellular signaling cascades. The Raf family of protein serine/threonine kinases plays a critical role in the regulation of cardiomyocyte survival and growth. The three Raf family members, Raf-1, B-Raf, and A-Raf, are highly homologous, and they are all expressed in the heart. Protein kinases of the Raf family phosphorylate and activate the mitogen-activated protein kinase kinases (MKKs, also known as MEKs). MKKs, in turn, are dual-specificity threonine and tyrosine kinases that phosphorylate and activate extracellular signal-regulated kinases (ERKs). ERKs phosphorylate a variety of substrates, including nuclear transcription factors, which regulate cell physiology. Raf proteins also have antiapoptotic activity that is independent of MKK and ERK. In this review, the role of Raf family members in the regulation of cardiomyocyte survival and growth will be discussed.

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

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