This model hyperplastic proliferation uses an activated form of Dmel\Ras85D in combination with a mutation affecting a gene in the Hippo signaling pathway; phenotypes are assayed in imaginal discs. Hippo signaling is compromised using a loss-of-function mutation of either Dmel\ex or Dmel\wts. Each mutation alone, including activated Ras85D, results in mild overproliferation phenotypes; the combination of activated Ras85D and reduced Hippo signaling results in extreme overgrowth phenotypes in discs.
Loss of ex does not fully abolish Hippo pathway activity; animals homozygous for LOF mutations exhibit mild overgrowth phenotypes in discs. Neither of the human genes orthologous to Dmel\ex, FRMD1 and FRMD6, has been introduced into flies.
Amorphic alleles of Dmel\wts are lethal. In wing discs, somatic clones carrying an amorphic mutation of wts exhibit an overgrowth phenotype. Both of the human orthologs of wts, Hsap\LATS1 and Hsap\LATS2, have been introduced into flies. Both human genes exhibit functional complementation (heterologous rescue), rescuing the lethal phenotype of wts knockdown effected by RNAi.
See the human disease model report 'cancer, multiple, Hippo signaling pathway' (FBhh0000764) and the pathway report 'Hippo Signaling Pathway' (FBgg0000917) for a listing of genes encoding core components and regulators of this pathway in flies. Multiple experiments support the model that the Hippo pathway regulates cell invasion by activating JNK signaling.
The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes). Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Animals carrying the Ras85DV12 activated allele typically die during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85DV12 exhibit an overgrowth phenotype in multiple different tissues tested.
[updated Jun. 2019 by FlyBase; FBrf0222196]