Possible interaction of IDGFs with the insulin pathway

Like other growth factors, the IDGFs presumably activate a signal transduction pathway that ultimately controls transcription and replication. One possibility is that they interact in some way with the insulin receptor (InsR) pathway, which has

FIG. 3. Expression of IDGF genes in the embryonic and larval fat body. Embryos and larval tissues (wholemounts) were used for in situ hybridization using digoxigenin-labelled antisense RNA probes. (A) Late embryo showing fat body expression of IDGF2. (B,C) Third-instar larval tissues showing fat body expression of IDGF3. IDGF1,2 and 3 show similar expression patterns at all three stages.

FIG. 3. Expression of IDGF genes in the embryonic and larval fat body. Embryos and larval tissues (wholemounts) were used for in situ hybridization using digoxigenin-labelled antisense RNA probes. (A) Late embryo showing fat body expression of IDGF2. (B,C) Third-instar larval tissues showing fat body expression of IDGF3. IDGF1,2 and 3 show similar expression patterns at all three stages.

been shown by several genetic studies to be involved in controlling imaginal disc growth in vivo (Weinkove & Leevers 2000). Neither insulin nor the IDGFs are effective alone, but the combination of these factors is effective in stimulating growth of imaginal disc cells in vitro. Although the Drosophila equivalent of insulin has not yet been reported, an insulin-like molecule has been detected in larvae using antibodies against mammalian insulin (Seecof & Dewhurst 1974, Meneses & De Los Angeles Ortiz 1975). Mammalian insulin is one of the requirements for the culture of imaginal disc cell lines in vitro (Cullen & Milner 1991) and it promotes growth of Drosophila cell primary cultures (Echalier 1997). An insulin-like hormone (prothoracicotropic hormone) has been identified in other insects and is produced by the endocrine system, but this protein does not activate the Drosophila InsR (Fernandez-Almonacid & Rosen 1987).

More is known about the Drosophila InsR and the downstream elements of this pathway. The receptor is expressed in imaginal discs (Garofalo & Rosen 1988), and is required for their normal growth (Chen et al 1996). It is a tetrameric glycoprotein with two a and two fl subunits (Fernandez-Almonacid & Rosen 1987) and as in the mammalian receptor, the fl subunit contains a transmembrane domain and a ligand-activated tyrosine kinase domain (Petruzzelli et al 1986, Nishida et al 1986). In mammalian cells, and probably in Drosophila as well, activation by ligand results in receptor autophosphorylation as well as recruitment of insulin receptor substrate proteins (encoded by chico in Drosophila) (Bohni et al 1999) to the receptor and subsequent phosphorylation of multiple tyrosine residues on the receptor and the substrate proteins. This triggers the activation of several signalling pathways including the Ras/MAP kinase pathway and the PI3K/PKB pathway (Yenush et al 1996).

The signal transduction pathway downstream of InsR seems to be well conserved in Drosophila compared to mammals, and to play an important role in controlling growth and body size (Weinkove & Leevers 2000). Overexpression of the insulin receptor in the developing eye imaginal disc causes enlargement of the eye in the adult, suggesting an increased growth rate of this tissue during the larval or pupal period (Huang et al 1999). Overexpression of wild-type Drosophila PI3K in vivo also leads to enlarged organs, and at least in the wing this is partly due to increased cell number (Leevers et al 1996). In contrast, overexpression ofthe PI3K target Dakt1 leads to increased cell size but does not affect cell number (Verdu et al 1999), so it is possible that the insulin receptor pathway divides between PI3K and Dakt1 into a branch that regulates cell size (via Dakt1 and S6 kinase) and one that regulates cell number (via unknown targets).

Expression of an activated form of Ras can also cause hyperplastic imaginal disc overgrowth (Karim & Rubin 1998), which might involve activation of the MAP kinase pathway. However, as with mammalian Ras, Drosophila Ras could also activate the downstream elements of the InsR pathway through direct interaction with PI3K (Weinkove & Leevers 2000). Additional pathway components must be identified in order to understand exactly how InsR signalling functions in controlling both cell size and cell proliferation in vivo. Direct studies of the interaction of the IDGFs with this pathway are also needed in order to understand the relationship between insulin and the IDGFs in controlling these processes.

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