TCL is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rho family of GTPases. TCL (TC10-like) shares 85% and 78% amino acid similarity to TC10 and Cdc42, respectively. TCL mRNA is 2.5 kb long and is mainly expressed in heart. In vitro, TCL shows rapid GDP/GTP exchange and displays higher GTP dissociation and hydrolysis rates than TC10. Like other Rac/Cdc42/RhoUV members, GTP-bound TCL interacts with CRIB domains, such as those found in PAK and WASP. TCL produces large and dynamic F-actin-rich ruffles on the dorsal cell membrane in REF-52 fibroblasts. TCL activity is blocked by dominant negative Rac1 and Cdc42 mutants, suggesting a cross-talk between these three Rho GTPases.
N-terminus Regulation TCL/RhoJ nucleotide exchange is influenced by amino acid regions outside of the nucleotide-bounding pocket though an allosteric regulation. One regulatory region is the N-terminus of TCL, which includes an extension of about 20 amino acids compared with Cdc42. Deletion of the TCL N-terminus produces a defect in GTP loading and exchange, with the effect mapped to the DEKK sequence consisting of Asp-17, Glu-18, Lys-19. A second regulatory sequence distal of TCL includes the R2c subregion, which contributes to TCL-specific nucleotide loading. In TC10 reverse chimeras' experiments, insertion of TCL R2c region resulted into impaired nucleotide binding, while the same region inserted into Cdc42 did not inhibit nucleotide exchange.
Disease Relevance Hypoxia induced TCL expression has been linked to an epigenetic pathway involving myocardial related transcription factors (MRTF-A) and histone acetyltransferase, hMOF. Under hypoxic conditions, MRTF-A activates hMOF which acetylates the TCL promoter, resulting in the increase of colorectal cancer cell migration and invasion. TCL is unrelated to TCL1A, a proto-oncogene implicated in the development of T-Cell Leukemias.
See also TCL1A
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