• carcinoma

This model of 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 or the larval ventral nerve cord. Hippo signaling is compromised using a loss-of-function mutations of Dmel\ex, Dmel\wts, Dmel\msn, or Dmel\Ptp61F. Mutations of ex, wts, Ptp61F, or activated Ras85D result in mild overproliferation phenotypes; mutation of msn does not result in an overproliferation phenotype. Mutations of ex, wts, msn, or Ptp61F that reduce Hippo signaling combined with activated Ras85D result in extreme overgrowth phenotypes in discs or the larval ventral nerve cord.

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. The fly cell line Ras[V12]-wts[RNAi] (FBtc0000189) has also been used in the context of this disease model.

Animals homozygous for loss-of-functions alleles of Dmel\msn typically die during the larval or pupal stage; somatic clones in the developing eye exhibit neuroanatomy defects. A number of human genes are orthologous to msn : TNIK, MINK1, and MAP4K4. Hsap\MINK1 has been introduced into flies, but has not been characterized.

Reduced expression of Dmel\Ptp61F, effected by RNAi, results in viable adults with increased body size, enlarged wing, decreased locomotive ability, slight developmental delay, and reduced lifespan. Ptp61F is ortholgous to two human genes, PTPN1 and PTPN2. Hsap\PTPN2 has been introduced into flies; heterologous rescue (functional complementation) has been demonstrated.

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, Ras85D^V12, 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\RRas85D die during the larval stage. Animals carrying the Ras85D^V12 activated allele typically die during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85D^V12 exhibit an overgrowth phenotype in multiple different tissues tested. For additional information and external links relevant to the role of RAS in human cancers see the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).

[updated Nov. 2023 by FlyBase; FBrf0222196]