Models of cancer have been developed using the Drosophila scrib gene (orthologous to human SCRIB) in combination with the Drosophila rolled (rl) gene (orthologous to human MAPK1). Somatic clones that are homozygous for scrib loss-of-function mutations exhibit overgrowth phenotypes; in combination with constitutively activated mutations of rl, more extreme hyperplastic phenotypes are observed.
The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The Drosophila scrib gene is a cell polarity regulator and neoplastic tumor suppressor; there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; the use of somatic clones has allowed characterization of LOF phenotypes in imaginal discs.
The human gene MAPK1 (mitogen-activated protein kinase 1, also known as ERK2) plays a key role in the MAPK/ERK kinase cascade and has been associated with multiple cancers. There is a single high-scoring ortholog is Drosophila, rolled (Dmel\rl), for which an extensive number of mutations, including classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\rl is also orthologous to the human gene MAPK3.
Mutations in MAPK1 and MAPK3 has been found in large-scale genome sequencing of human tumors. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R80S in the fly rlgene (corresponds to R67I in the human MAPK1 gene and to R84H in the human MAPK3 gene); D334N in the fly rlgene (corresponds to D321N in the human MAPK1 gene. In scrib LOF clones, expression of either the R80S variant or the D334N variant results in hyperplastic phenotypes more pronounced than with scrib mutants alone. The two variants in combination produce a more extreme hyperplastic phenotype (in the scrib mutant background).
See also the human disease models ‘cancer, multiple, MAPK1,3-related’ (FBhh0001186) and ‘cancer, epithelial, SCRIB-related’ (FBhh0000587).
[updated Aug. 2020 by FlyBase; FBrf0222196]
Mutations at the amino acids analogous to R80 in Drosophila have been found in large-scale genome sequencing of human tumors: R84H in MAPK3, catalogue of somatic mutations in cancer (COSMIC) ID: 4875437; and R67I in MAPK1, COSMIC ID: 6946407. A mutation analogous to D334N has also been observed: D321N in MAPK1, COSMIC ID: 98175 (FBrf0244504 and references cited therein).
MAPK1 and MAPK3 encode serine/threonine kinases that are members of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. MAPK1 (ERK2) and MAPK3 (ERK1) play key roles in this cascade. The activation of MAPK1 or MAPK3 kinase requires its phosphorylation by upstream kinases; upon activation, the MAP kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. [Gene Cards, MAPK3, MAPK1; 2018.07.11]
Many to one (2 human to 1 Drosophila); multiple more distantly related genes in both species. Dmel\rl is most closely related to MAPK1 and MAPK3.
Many to one (2 human to 1 Drosophila); multiple more distantly related genes in both species. Dmel\rl is most closely related to MAPK1 and MAPK3.
Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.
High-scoring ortholog of human MAPK1 and MAPK3 (1 Drosophila to 2 human); multiple more distantly related genes in both species. Dmel\rl shares 76-82% identity and 84-90% similarity with the human genes.
Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.
