Actin-dependent activation of serum response factor in T cells by the viral oncoprotein tip

Serum response factor (SRF) is widely expressed in both invertebrates and vertebrates. SRF plays an essential role in embryogenesis, but is also involved in multiple processes in developed organisms including neuronal and muscle cell function.SRF binds as a dimer to a specific DNA sequence known as the CArG box in the promoter of hundreds of target genes. Selective binding is determined by interactions with more than 60 different cofactors, which turn SRF into a versatile transcription factor translating cell- and stimulus-specific signaling into selective target gene expression [1,2].Well-known SRF cofactors are members of the ternary complex factor (TCF) family of Ets domain proteins, like Elk-1, SAP-1 and Net. They are regulated by phosphorylation via the classical mitogen-activated protein kinase (MAPK) pathway involving the GTPase Ras, which activates the serine-threonine kinases Raf, MEK and ERK. Their recruitment to DNA depends on a defined DNA sequence, called Ets motif (C/A)(C/A)GGA(A/T), next to the SRF-binding CArG box [3,4]. A serum response element (SRE), first described in the c-fos promoter, contains an Ets motif adjacent to the CArG box [5].Another group of SRF cofactors are the myocardin-related transcription factors (MRTFs). Myocardin, the founding member of this family, is selectively expressed in cardiac and smooth muscle cells and constitutively binds SRF. In contrast, MRTF-A (MAL, MKL1, BSAC) and MRTF-B (MAL16, MKL2) are widely expressed in many cell types [6]. Their cofactor function is controlled by GTPases of the Rho family (RhoGTPases), which are considered as important regulators of the actin cytoskeleton. Activation of the RhoGTPases RhoA, Rac1 and Cdc42 results in the formation of focal adhesion complexes, lamellipodia and filopodia, respectively [7]. These processes involve actin polymerization and thereby reduce the levels of monomeric, globular actin (G-actin). G-actin binds to N-terminal RPEL motifs of MRTF and thereby sequesters and