Kinase Family Trbl

Kinase Classification: Group CAMK: Family Trbl

Trbl ("tribbles") is a family of pseudokinases involved in protein interactions and ubiquitination.

Evolution

Trbl is found throughout animals. Nematodes have a highly divergent member, originally classified as Other-Unique. Vertebrates have 3, TRIB1, TRIB, TRIB3. TRIB3 is substantially more divergent and fast-evolving in sequence than TRIB1 or TRIB2, and appears to have more divergent functions.

Domain Structure

Trbl has a divergent kinase domain, followed by a MEK1-binding motif (ILDHPWF in human TRIB2), a COP1 degron (DQLVP in human TRIB2), and a unique C-terminal tail. The COP1 domain is degraded in nematodes and in some insects that have lost COP1, including Drosophila, and the MEK1 motif is also degraded in those same insects and in nematodes.

Functions

Trbl has a variety of functions, mostly as a modulated scaffold that brings other proteins together.

In Drosophila, trbl binds binds and degrades a number of proteins, including the cdc25 phosphatase string, to control cell cycle, and the C/EBP protein slbo, to control cell migration. Mammalian Trib1 and Trib2 also bind C/EBP proteins CEBPA and CEBPB to cause their degradation [1], while TRIB3 binds to CDC25A [2] and TRIB2 binds to CDC25B and CDC25CC [3]; in both cases, binding leads to proteasomal degradation. Trbl-Akt interaction is also seen in both Drosophila and human [4, 5].

Modulation of CEBP function is conserved in C. elegans, helping to define the highly divergent gene nipi-3 (K09A9.1) as a member of the Trbl family [6, 7].

References

1. Yokoyama T and Nakamura T. Tribbles in disease: Signaling pathways important for cellular function and neoplastic transformation. Cancer Sci. 2011 Jun;102(6):1115-22. DOI:10.1111/j.1349-7006.2011.01914.x |
2. Sakai S, Ohoka N, Onozaki K, Kitagawa M, Nakanishi M, and Hayashi H. Dual mode of regulation of cell division cycle 25 A protein by TRB3. Biol Pharm Bull. 2010;33(7):1112-6. DOI:10.1248/bpb.33.1112 |
3. Liang KL, Paredes R, Carmody R, Eyers PA, Meyer S, McCarthy TV, and Keeshan K. Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C. Int J Mol Sci. 2016 Aug 23;17(9). DOI:10.3390/ijms17091378 |
4. Naiki T, Saijou E, Miyaoka Y, Sekine K, and Miyajima A. TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta. J Biol Chem. 2007 Aug 17;282(33):24075-82. DOI:10.1074/jbc.M701409200 |
5. Das R, Sebo Z, Pence L, and Dobens LL. Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. PLoS One. 2014;9(10):e109530. DOI:10.1371/journal.pone.0109530 |
6. Kim KW, Thakur N, Piggott CA, Omi S, Polanowska J, Jin Y, and Pujol N. Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development. BMC Biol. 2016 Dec 7;14(1):104. DOI:10.1186/s12915-016-0320-z |
7. McEwan DL, Feinbaum RL, Stroustrup N, Haas W, Conery AL, Anselmo A, Sadreyev R, and Ausubel FM. Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway. BMC Biol. 2016 Dec 7;14(1):105. DOI:10.1186/s12915-016-0334-6 |