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Figure 2 | Skeletal Muscle

Figure 2

From: The myogenic kinome: protein kinases critical to mammalian skeletal myogenesis

Figure 2

Regulation of the early myogenic transcriptional program by the kinome. The figure shows the mechanisms by which the kinases described in the text coordinate embryonic precursor activation, myoblast proliferation and the prevention of premature myoblast differentiation. Wnt1 and Wnt7a stimulation of precursor cells activates protein kinase A (PKA), which, through the phosphorylation of CREB, induces the expression of the myogenic transcription factors Myf5, MyoD and Pax3, resulting in the myogenic commitment of embryonic precursors. PKA then prevents the premature differentiation of proliferating myoblasts by phosphorylating and inhibiting the transcriptional activity of MEF2D. The cyclin-dependent kinases (CDKs) regulate cell cycle transitions and are activated at the appropriate time by the availability of their respective cyclins, depicted in the boxed inset. Cell cycle progression is achieved by the CDKs through the phosphorylation of Rb, which, when phosphorylated, is unable to bind and inhibit the E2F family of transcription factors that promote the expression of genes involved in cell division. Phosphorylation of Rb by the CDKs also prevents it from associating with and transactivating MyoD, thereby inhibiting cell cycle exit and differentiation. Cell cycle exit is further prevented by the proteolytic degradation of MyoD that results from direct CDK phosphorylation. The extracellular signal-regulated kinase (ERK) is activated by growth factors such as fibroblast growth factor and insulin-like growth factor (IGF), although the substrates ERK acts on to promote proliferation and inhibit differentiation are unknown. IGF also activates the Akt1 pathway and stimulates proliferation when myoblasts are subconfluent. Phosphorylation of FoxO1 by Akt1 prevents this transcription factor from accumulating in the nucleus, inhibiting the expression of genes involved in cell cycle exit, such as p27.

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