14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila.
Genetic control of growth is an essential feature of development in all multicellular organisms. Translationally controlled tumor protein (Tctp) is a conserved protein family implicated in cancer. Despite its roles in cell death and proliferation, it is largely unknown how Tctp function is regulated. We have used Drosophila melanogaster, the fruit fly, as a genetic model to delineate the function of Tctp in vivo. Here, we have genetically identified the 14-3-3 genes as interacting partners of Tctp. Work carried out by researchers at KAIST reveals that 14-3-3s promote the interaction between Tctp and Rheb, two regulators of TOR (Target of rapamycin) signaling. This study provides a novel mechanism of 14-3-3s in growth regulation.
Tctp was initially identified in cancer cell lines as a highly upregulated protein. Reducing the Tctp level in cancer cells results in tumor reversion, indicating the importance of Tctp regulation. In contrast to extensive cell culture studies, the function of Tctp in animals is not well understood. In this study, the researchers searched for new genes that can interact with Tctp, using a strategy called a “genetic modifier screen” in Drosophila. This approach was based on the assumption that mutations in two interacting genes can result in much stronger, or weaker, phenotypes than those seen for a single mutation. In this screen, they found that partial loss of Tctp results in smaller eyes than the normal, but reducing both Tctp and the 14-3-3 leads to much smaller eyes (Figure 1d), hence identifying 14-3-3 genes as genetic interactors of Tctp.
It is well known that 14-3-3 proteins are important adaptor molecules that modulate diverse signaling pathways. Functional analysis of 14-3-3 proteins in mammals has been complicated due to the presence of multiple isoforms that are functionally redundant. In contrast, Drosophila has only two isoforms called 14-3-3 and 14-3-3. The researchers showed that loss of either one of the 14-3-3 isoforms does not cause significant growth defects in the eye and head. However, when both isoforms were removed, this resulted in headless flies (Figure 2d). This result indicates that 14-3-3and 14-3-3 are functionally redundant; however, loss of both isoforms is detrimental to organ growth.
An intriguing question then arose: how does partial reduction of either one of the 14-3-3 isoforms cause strong impacts on organ growth when Tctp levels are low? This phenotypic synergy was a clear indication of a strong linkage between 14-3-3 and Tctp. Previously, we have shown that Tctp interacts with Rheb, an activator of TOR signaling important for cell growth. Consistent with the Tctp-Rheb interaction, similar genetic interactions were found to exist between 14-3-3 and Rheb. An obvious implication was that 14-3-3s may be necessary as adaptors for the association between Tctp and Rheb. Indeed, data show that loss of both 14-3-3 isoforms abolishes Tctp-Rheb binding, whereas loss of a single 14-3-3 isoform does not. This biochemical redundancy of 14-3-3 isoforms is also in line with their functional redundancy in organ growth. Taken together, 14-3-3s potentially function as a matchmaker for Tctp and Rheb to promote growth signaling (Figure 2e).
The significance of this study lies in the identification of a new regulatory function for 14-3-3s in growth signaling in vivo. Since abnormal regulation of Tctp and TOR signaling can lead to cancers, mechanistic understanding of their interaction with 14-3-3 can help elucidate the molecular basis of such diseases. Regulatory interaction between 14-3-3 and TOR components also illustrates the importance of cross-talk between genes, providing insights into synergistic effects in many genetic disorders.
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