A Versatile Transcriptional Effector of Wingless Signaling

As found in mammalian cells, the interaction between Zw-3 and Arm is actually more complex. There is yet another player in regulating Arm, the tumor suppressor gene APC. The APC protein binds to Arm and accelerates Arm turnover. APC also binds to Zw-3 and is in fact a better substrate for Zw-3 than Arm. A complex between these three proteins may keep Arm levels low (Figure 2Figure 2) (Rubinfeld et al. 1996xRubinfeld, B, Albert, I, Porfiri, E, Fiol, C, Munemitsu, S, and Polakis, P. Science. 1996; 272: 1023–1026Crossref | PubMedSee all ReferencesRubinfeld et al. 1996). APC, E-cadherin, and TCF can all bind to the middle domain of Arm, the part that contains a stretch of 13-fold repeated sequences, but each partner binds to a specific subset of these repeats (Figure 1Figure 1). Possibly, there is some competition for binding, and binding by one or the other partners is subject to some regulation.APC traces its history to tumors found in familial colon carcinomas; it is a tumor suppressor gene that is deleted in tumors or in germ line DNA. The findings on interactions between Arm and TCF have also led to a much better understanding of the mechanism of tumorigenesis by loss of APC. Korinek et al. 1997xKorinek, V, Barker, N, Morin, P.J, van Wichen, D, de Weger, R, Kinzler, K.W, Vogelstein, B, and Clevers, H. Science. 1997; 275: 1784–1787Crossref | PubMed | Scopus (2447)See all ReferencesKorinek et al. 1997 show that several colon carcinoma lines, derived from tumors with APC deletions, contain a complex between one of the human TCF homologs (hTCF-4) and Arm. This complex activates expression of reporter constructs, indicating that the loss of APC function in these cells releases enough Arm to team up with TCF to become a transcriptional activator. As predicted from the model in which APC is a gatekeeper of Arm, transfection of full-length APC into those cells inhibits expression of the reporter gene constructs. Mutant forms of APC, when transfected, are incapable of blocking target gene expression.These experiments provide a plausible explanation of how loss of APC can activate gene expression and lead to cell transformation (although no target genes in oncogenesis are known). A surprise came when Morin et al. 1997xMorin, P.J, Sparks, A.B, Korinek, V, Barker, N, Clevers, H, Vogelstein, B, and Kinzler, K.W. Science. 1997; 275: 1787–1790Crossref | PubMed | Scopus (2794)See all ReferencesMorin et al. 1997 found several colon carcinoma cell lines with normal levels of wild-type APC but nevertheless displaying strong expression of these reporter constructs). It appeared that Arm in those cells had found another way to escape from APC control: by mutations in its own gene. These mutations are also present in several melanoma (18xRobbins, P.F, El-Gamil, M, Li, Y.F, Kawakami, Y, Loftus, D, Appella, E, and Rosenberg, S.A. J. Exp. Med. 1996; 183: 1185–1192Crossref | PubMed | Scopus (380)See all References, 20xRubinfeld, B, Robbins, P, El-Gamil, M, Albert, I, Porfiri, E, and Polakis, P. Science. 1997; 275: 1790–1792Crossref | PubMed | Scopus (987)See all References) and are of a special class: they eliminate specific amino acids in the amino-terminal domain of the protein, in particular residues that become phosphorylated prior to the proteolytic down-regulation of Arm (Figure 1Figure 1). Hence, Arm can turn into an oncogene in its own right. A question that remains, however, is whether TCF is required for cell transformation by loss of APC or mutations in Arm. A testable prediction of the models emerging from these papers is that a dominant negative TCF should revert the transformed phenotype.It is now fairly common to find signal transduction pathways conserved in evolution or to find components in these critical growth-controlling mechanisms mutated in tumors. Nonetheless, the discoveries summarized here form yet another spectacular and exciting example of these principles. Yet, one piece is missing: a genetic function of APC in Drosophila. A fly APC homolog was recently identified, but based on its expression and a preliminary mutant analysis, APC does not participate in Wg signaling (Hayashi et al. 1997xHayashi, S, Rubinfeld, B, Souza, B, Polakis, P, Wieschaus, E, and Levine, A.J. Proc. Natl. Acad. Sci. USA. 1997; 94: 242–247Crossref | PubMed | Scopus (106)See all ReferencesHayashi et al. 1997). This assumes that the gene is not redundant or maternally provided, but it points to interesting alternative pathways. Further genetic tests of this signaling system in cancer cells, flies, and worms, combined with cell biological experiments, will undoubtedly add more to this rapidly developing story.