**5. Synopsis**

Recent years have seen a considerable deepening of our insight into the multiple biological functions of TCTP/fortilin/HRF, into the mechanisms of its regulation and into how dysregulation of the protein may contribute to various disease processes. At the cellular level, we learned more about the role of TCTP in the cell division process, both mitotic and meiotic; its function in stabilising polar spindle microtubules and the importance of the mitotic phosphorylation of TCTP by Plk1 for its detachment from the spindle. A novel mechanism for cell cycle control by TCTP was recently discovered in plants and insects. TCTP interacts with the CSN4 subunit of the COP9 signalosome complex to regulate cell cycle progression at the G1/S transition, through modification of the activity of Cullin–Ring ubiquitin ligases. This is important in both cell proliferation and organ development; however, the relevance of deregulation by this mechanism in diseases is ye<sup>t</sup> to be documented. The importance of TCTP in organ development was further confirmed by additional examples in insects (tissue regeneration), in vertebrates (nervous system development) and in plants (lateral root formation).

The association of TCTP with the protein synthesis machinery was further consolidated by the discovery of its interaction with the additional ribosomal factors, EF1A2 and RACK1, as well as with mRNAs. Detailed structural studies confirmed that the previously reported binding of TCTP to EF1B is the most conserved interaction of TCTP. However, it is still an open question, whether TCTP a ffects protein synthesis rates generally, and/or modulates the translation of specific mRNAs. We certainly know several examples of TCTP regulating the stability of individual proteins.

The function of TCTP as a cytoprotective protein is well established, and several additional examples have now been reported. As a new mechanism, the involvement of TCTP in the unfolded protein response to prevent ER-stress was recently revealed. Autophagy is another important cell-homeostatic mechanism, and a few papers described the involvement of TCTP in this process as well, although the precise e ffect of TCTP on autophagy is still a matter of debate.

Cellular TCTP levels are highly regulated in response to alterations of a variety of cell physiologic conditions. We learned more about regulatory mechanisms that are involved in modulating TCTP levels. The list of transcription factors regulating TCTP mRNA synthesis has been extended by the tumor suppressor protein p53 and by IRE-BP1, an insulin-responsive transcription factor. We now know several translational control mechanisms, which may modulate the translational e fficiency of TCTP mRNA; these are (1) signalling through the mTORC1 pathway, e.g., during growth induction of TCTP synthesis, (2) negative regulation by PKR in stress conditions, (3) mRNA stability regulation in Trypanosomes and (4) regulation through a small number of microRNAs in cancer. Several examples were reported, showing that TCTP levels may be modulated through regulated protein degradation. In serum starvation, TCTP was found to be degraded through chaperone-mediated autophagy.

The involvement of TCTP in cancer has been repeatedly proven. More examples of high TCTP levels being associated with a poor outcome in cancer patients have been reported. The participation of TCTP in the following cancer-promoting pathways has been demonstrated: the mTOR pathway and cell cycle progression, DNA repair and genome stability, antagonism to tumor suppressor p53 and anti-apoptotic activity, maintenance of 'stemness' in cancer cells, promotion of EMT and involvement in metastasis, and development of radio- and chemoresistance in cancer cells. Initial ideas to target TCTP as (part of) potential anti-cancer strategies have been published. Other disease processes, where dysregulation of TCTP might be a contributing factor, include cardiovascular diseases (arthrosclerosis and hypertension) and metabolic disorders (diabetes, muscle hypertrophy). The extracellular function of dimerised TCTP as histamine-releasing factor (HRF) in allergic and immune disorders has been further clarified, for asthma, atopic dermatitis, food allergy, and chronic urticaria.

With this extended knowledge about the principal functions of TCTP/fortilin/HRF in many biological and disease processes, our 'toolbox' should be large enough now for taking first steps towards 'translating' this knowledge into practical medical applications.

**Author Contributions:** U.-A.B. conceived the review; both authors wrote the article and corrected the final version. All authors have read and agreed to the published version of the manuscript.

**Funding:** U.-A.B. was supported by grants from the Wellcome Trust (UK) and by small grants from the Illawarra Health and Medical Research Institute and from the Graduate School of Medicine, University of Wollongong, NSW, Australia. A.T. was supported by grants from the French National Agency for Research ANR (ANR-09-BLAN-0292), the European Union Network of Excellence CONTICANET, LabEx LERMIT, INCa Projets libres de 2013-1-PLBIO-10-IGR-1.

**Acknowledgments:** AT thanks Robert Amson for the past present and future work done together.

**Conflicts of Interest:** The authors declare no conflict of interest.
