Epigenetics and Signaling Pathways in Glaucoma

Figure 1

TGF- signaling pathways. TGF- increases extracellular matrix production through the Rho-GTPase/Rho kinase, Smad, and MAP kinase pathways. TGF- binds to TGF- receptors I and II, triggering autophosphorylation. This activates RhoGEF, which attaches a GTP to RhoA. RhoA activates Rho kinase, which leads to the phosphorylation of myosin light chain (MLC). This leads to stress fiber organization, cell contraction, extracellular matrix organization, and the expression of genes for -smooth muscle actin and extracellular matrix production. In the Smad pathway, TGF- binding triggers TGF- receptor I to phosphorylate Smad2 and Smad3, which form a Smad Complex with Smad4. The complex travels to the nucleus, where it helps transcribe genes for extracellular matrix production. TGF- activates the MAP kinase pathway by causing autophosphorylation of the tyrosine residues on TGF- receptor II. This recruits Shc, Grb2, and SOS. SOS activates the GTPases Ras or Rac1. Ras activates Raf, which triggers MEK1 and subsequently ERK 1/2 activation. ERK 1/2 can increase PAI-1 expression in human trabecular meshwork cells, which increases extracellular matrix production. The GTPase Rac1 activates p21-activated kinase (PAK), which activates MAP kinase kinase (MKK) 3/6, which activates p38. This induces expression of Interleukin 6 and SPARC.