TCL (GTPase)

TCL is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rho family of GTPases.[1][2]

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.[3]

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.[4]

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.[4]

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.[5]

TCL is unrelated to TCL1A, a proto-oncogene implicated in the development of T-Cell Leukemias.

See also

References

  1. ^ Ridley A. (2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends Cell Biol. 16 (10): 522–9. doi:10.1016/j.tcb.2006.08.006. PMID 16949823.
  2. ^ Boureux A, Vignal E, Faure S, Fort P (2007). "Evolution of the Rho family of ras-like GTPases in eukaryotes". Mol Biol Evol. 24 (1): 203–16. doi:10.1093/molbev/msl145. ISSN 0021-9193. PMC 2665304. PMID 17035353.
  3. ^ Vignal E, De Toledo M, Comunale F, Ladopoulou A, Gauthier-Rouviere C, Blangy A, Fort P (2007). "Characterization of TCL, a new GTPase of the rho family related to TC10 and Ccdc42". J Biol Chem. 275 (46): 36457–64. doi:10.1074/jbc.M003487200. ISSN 0021-9258. PMID 10967094.
  4. ^ a b Florke, Rebecca R.; Young, Grace T.; Hamann, Michael J. (2020-03-03). "Unraveling a model of TCL/RhoJ allosterism using TC10 reverse chimeras". Small GTPases. 11 (2): 138–145. doi:10.1080/21541248.2017.1347599. ISSN 2154-1248. PMC 7053938.
  5. ^ Chen, Baoyu; Fan, Zhiwen; Sun, Lina; Chen, Junliang; Feng, Yifei; Fan, Xiangshan; Xu, Yong (2020-09-30). "Epigenetic activation of the small GTPase TCL contributes to colorectal cancer cell migration and invasion". Oncogenesis. 9 (9). doi:10.1038/s41389-020-00269-9. ISSN 2157-9024. PMC 7528090. PMID 32999272.


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