Tribbles Homolog 2 (Trib2), a Pseudo Serine/Threonine Kinase In

Fang et al. Cell Commun Signal (2021) 19:41 https://doi.org/10.1186/s12964-021-00725-y REVIEW Open Access Tribbles homolog 2 (Trib2), a pseudo serine/ threonine kinase in tumorigenesis and stem cell fate decisions Yu Fang1,2*, Angelina Olegovna Zekiy3, Farhoodeh Ghaedrahmati4, Anton Timoshin5, Maryam Farzaneh6 , Amir Anbiyaiee7 and Seyed Esmaeil Khoshnam8 Abstract The family of Tribbles proteins play many critical nonenzymatic roles and regulate a wide range of key signaling pathways. Tribbles homolog 2 (Trib2) is a pseudo serine/threonine kinase that functions as a scafold or adaptor in various physiological and pathological processes. Trib2 can interact with E3 ubiquitin ligases and control protein stability of downstream efectors. This protein is induced by mitogens and enhances the propagation of several cancer cells, including myeloid leukemia, liver, lung, skin, bone, brain, and pancreatic. Thus, Trib2 can be a predictive and valuable biomarker for the diagnosis and treatment of cancer. Recent studies have illustrated that Trib2 plays a major role in cell fate determination of stem cells. Stem cells have the capacity to self-renew and diferentiate into specifc cell types. Stem cells are important sources for cell-based regenerative medicine and drug screening. Trib2 has been found to increase the self-renewal ability of embryonic stem cells, the reprogramming efciency of somatic cells, and chondrogenesis. In this review, we will focus on the recent advances of Trib2 function in tumorigenesis and stem cell fate decisions. Keywords: Pluripotent stem cells, Tribbles homolog 2, Tumorigenesis, Pluripotency, Reprogramming, Stem cell fate, Regenerative medicine Background E3 ubiquitin ligases and control protein stability of down- Tribbles homolog 2 (Trib2) is a pseudo serine/threo- stream efectors [7]. Trib2 as a mitosis blocker regulates nine kinase and a member of the Tribbles family that various cellular processes, including germ cell devel- functions as a scafold or adaptor in signaling pathways opment, apoptosis, proliferation, lineage specifcation, in a number of physiological and pathological processes reproduction, infammation, innate immunity, and drug [1–3]. Te family of Tribbles proteins play many criti- resistance [8–11]. It is known that Trib2 has diverse roles cal nonenzymatic roles and regulate a wide range of key in neurological disorders, metabolic diseases, autoim- signaling pathways such as mitogen-activated protein mune and infammatory diseases, arthritis, and a number kinase (MAPKs), nuclear factor-κB (NF-kB), PI3K/AKT, of cancers (chronic myeloid leukemia, liver, melanoma, and activating transcription factor 4 (ATF4) in healthy and ovarian) [3, 12, 13]. In human cancer, Trib2 as a and pathological processes [4–6]. Trib2 can interact with cancer-associated pseudokinase and novel oncogene can enhance cell proliferation and stimulate cell cycle arrest *Correspondence: 01693@aynu.edu.cn [14]. Trib2, recently identifed as the cause of cancer 1 Anyang Center for Chemical and Pharmaceutical Engineering, College drug resistance [15, 16]. Tere is substantial evidence of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, Henan, People’s Republic of China that Trib2 can be a predictive and valuable biomarker for Full list of author information is available at the end of the article cancer diagnosis and treatment [6, 17]. Recent studies © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fang et al. Cell Commun Signal (2021) 19:41 Page 2 of 8 have illustrated that Trib2 plays a major role in cell fate Little information is known about the role of Trib2 in determination of stem cells [2]. Stem cells are undifer- mammals [9, 27]. Trib2 has a low afnity for ATP and entiated cells that have the capacity to self-renew and dif- further structural studies are required for the ATP-bind- ferentiate into specifc cell types [18, 19]. Stem cells are ing status of this protein [6, 14]. Trib2 via a ubiquitin- classifed into pluripotent (embryonic stem cells (ESCs) and proteasome-dependent pathway regulates the cell and induced pluripotent stem cells (iPSCs)), multipo- cycle in human cells [31, 36]. It should be noted that both tent (mesenchymal stem cells (MSCs) and hematopoi- the Trib2 kinase domain and COP1 binding are essential etic stem cells (HSCs)), and unipotent stem cells [20–22]. for the ability of Trib2 to degrade C/EBPα [37]. Trib2 has Human PSCs and MSCs are important sources for cell- been reported to be a pro-apoptotic molecule that stimu- based regenerative medicine, tissue engineering, and lates apoptosis via a caspase-dependent mechanism [38]. drug screening [23–25]. Trib2 has been found to increase Trib2 with the expression of pro- and anti-infammatory the self-renewal ability of ESCs, the reprogramming ef- immune modulators appears to be essential for innate ciency of somatic cells, and chondrogenesis [2]. In this immunity [39]. Trib2 as an important regulator of nor- review, we will focus on the recent advances of Trib2 mal hematopoiesis can regulate the diferentiation poten- function in tumorigenesis and stem cell fate decisions. tial of intrathymic precursors and the checkpoints of thymopoiesis [11]. Te function of monocytes and mac- Structure and function of Trib2 rophages can be modulated by Trib2 [40, 41]. Trib2 has Tribbles (Trib) is a critical regulator of embryonic devel- been shown to regulate the development of T-cell and opment that for the frst time identifed in Drosophila erythroid cells [42, 43]. Tis protein as an anti-infamma- [26]. In the human genome, the Trib proteins have three tory factor negatively regulates NF-κB (p100) activity in homologs, including TRIB1, TRIB2, and TRIB3, with the TLR5 pathway [9, 44]. During follicular development, a single kinase-like and highly conserved domain that Trib2 increases the activity of the MAPK/ERK pathway encodes pseudo-kinase proteins [9]. Trib2 contains an and regulates granulosa cells (GCs) proliferation and N-terminal domain (PEST), a C-terminal E3 ligase-bind- function [45]. ing domain, and a pseudokinase domain with a Ser/Tr protein kinase-like domain (without a canonical ‘DFG’ Diferent roles of Trib2 in tumorigenesis (metal-binding) motif) [1, 26]. Trib2 is a cancer-associated pseudokinase that can be Te C-terminal domain has the HPW [F/L] motif (tar- induced by mitogens and enhances the propagation of gets MAPKK/MEK family members) and the conserved several cancer cells, including myeloid leukemia, liver, DQXVP [D/E] peptide motif (binds to COP1 E3 ubiqui- lung, skin, bone, brain, and pancreatic [10, 46] (Table 1). tin ligases) [27]. Te pseudokinase domain has a unique In normal murine hematopoiesis, TRIB2 function is cysteine-rich C-helix that binds with E3 ubiquitin ligases necessary for the thymopoietic reaction to oncogenic [28] (Fig. 1). stress [47]. In hematological malignancies, TRIB2 as a TRIB proteins through E3 ligase-dependent ubiquitina- target gene of MEIS1, E2F1, and NOTCH1 participates in tion (pseudokinase mechanism) and scafolding (with the acute myeloid leukemia (AML) and T cell acute lympho- MAPK and AKT pathway) have the potential to control blastic leukemia (T-ALL) [42, 48, 49]. In human AML, cell proliferation, apoptosis, survival, and diferentiation Trib2 has been reported to be a negative regulator of C/ [27]. Te family of Tribbles proteins can regulate a wide EBPα expression and enhances AML progression [50]. In range of signaling pathways such as mitogen-activated patient-derived human AML cells, Trib2 enhances the protein kinase (MAPKs), nuclear factor-κB (NF-kB), pro- expression of anti-apoptotic B-cell lymphoma 2 (BCL2) tein kinase B (PKB or AKT), and activating transcription [51]. In chronic myelogenous leukemia (CML), Trib2 factor 4 (ATF4) [4–6]. In the Toll-like receptor (TLR) through the ERK pathway increases cell proliferation and signaling pathway, Trib1 negatively controls the expres- drug resistance [12]. Smad ubiquitination regulatory fac- sion of CCAAT/enhancer-binding protein β (C/EBPβ) tor 1 (Smurf1) is a HECT-type E3 ubiquitin ligase that [29]. Trib1 and Trib2 are able to recruit the E3 ligase and acts as a tumor enhancer or suppressor in various bio- induce C/EBPα and C/EBPβ degradation [30, 31]. Tere- logical processes [52]. Trib2 by regulating the degrada- fore, TRIBs through the degradation of C/EBP transcription of E3 ubiquitin ligase βTrCP, COP1, and Smurf1 can tion factors promote oncogenesis [6]. Trib3 has been inhibit the Wnt pathway and reduce cell propagation in shown to regulate serine-threonine kinase AKT (PKB), myeloid leukemia [53]. In response to stress, TRIB2 as a p65/rel A, and activating ATF4 [32–34]. Trib1 and Trib3 tumor suppressor stimulates activation of p38 stress sign- in response to various pro-infammatory stimuli trigger aling in myeloid leukemia [54]. Tus, Trib2 may decrease the MAP kinase pathway and regulate the activator pro- the ability of leukaemia cells to propagate [54]. In T-ALL, tein 1 (AP-1)-related pathway [35].

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