BAMBI

BAMBI associates with the cytoplasmic domain of T RI receptors in the absence of ligand (Figure 20.6e). In so doing, it prevents phosphorylation of T RI and inhibits signalling from activin, BMP, and TGF .30

Downstream signalling: Drosophila, Caenorhabitidis, and Smad

Genetic screens of accessible organisms such as Drosophila and C. elegans have provided pointers to the mechanism of TGF signalling in mammalian cells. The gene decapentaplegic (Dpp), when mutated, causes pattern deficiencies and duplications in structures derived from one or more of the 15 major imaginal disks in Drosophila.31 Dpp, equivalent to BMPs-2

and 4 of mammalian cells, is responsible for dorsal/ventral polarity in early development. Later, with the appearance of the segments, Dpp functions in the definition of boundaries between the segmental compartments. As part of this process, it defines the position of the future limbs, wings, legs, and antennae. It also has a role in the structuring of the mesoderm (see web page http://www.sdbonline.org/fly/aimain/1aahome.htm)

The Dpp gene product acts through three receptors that are homologous to the family of mammalian TGF receptors (thickveins, saxophone (T RI), and punt (T RII)). Genetic screening has revealed a mutation that, when combined with Dpp mutations associated with a feeble phenotype, generates one that is more severely affected. The mutant gene so obtained, Mad, yields flies that exhibit defects resembling those due to mutated Dpp.32 However, since wildtype Dpp cannot restore the defects induced by mutations in Mad, Dpp must lie upstream of Mad (Figure 20.7).33

Decapentaplegic, paralysed at 15 sites.

Imaginal, from imago, the final and perfect stage or form of an insect after its metamorphoses.

Fig 20.7  Signal transduction pathways downstream of serine/ threonine kinase receptors in two phyla.

Homologies between the genes implicated in these pathways has allowed the elucidation of the sequence of events downstream of the TGF receptor in mammals.