Loss of apical-basal polarity is an early event in the development of epithelial cancers. Epithelial cell polarity is maintained by three highly conserved polarity complexes, Par, Crumbs (CRB) and Scribble (SCRIB). In Drosophila, the Par complex consists of Dmel\baz (PARD3, PARD3B in human), Dmel\Cdc42 (CDC42 in human), Dmel\par-6 (PARD6A, PARD6B, PARD6G in human) and Dmel\aPKC (PRKCI, PRKCZ in human). This complex is variously called the PAR3-aPKC-PAR6 complex, the Cdc42-Par6-aPKC complex, the aPKC-PAR complex, or other combinations of the components; the junctional apical-basal polarity complex or the junctional ABP complex. The four component fly genes have been extensively studied: classical loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for each; physical and genetic interactions have been described for each; see below and in the respective gene reports.
The human Hsap\CDC42 and Hsap\PARD6B genes have been introduced into flies, but have not been characterized in context of this disease model.
Assayed in imaginal discs in flies, loss-of-function mutations of the Par complex genes exhibit polarity and other epithelial defects, but do not result in overgrowth phenotypes. Early work in Drosophila demonstrated that loss-of-function mutations of baz or Cdc42, in combination with a Ras85D activated mutation, transform the activated Ras overproliferation phenotype into an invasive phenotype.
Drosophila larval wing imaginal discs undergo apoptosis-induced compensatory proliferation following tissue injury; this can be assayed by exposing larvae to irradiation. Loss of Cdc42, and to a lesser extent aPKC, increase this proliferation response. Cdc42, baz, aPKC, and par-6 have been characterized in combination with the anti-apoptotic p35 gene from baculovirus (BacA\p35). When apoptosis is blocked by p35 expression, Par-complex-depleted tissues are hyperproliferative, leading to tissue and organ overgrowth.
Activated aPKC expressed in wing discs has been used in transplantation assays; hosts develop malignant tumors. Reduced lifespan is observed, in part due to impact on the blood-brain barrier. Data suggest that transplanted tumors actively induce blood-brain barrier permeabilization; preventing the increased blood-brain barrier permeabilization extends the host lifespan.
[updated Oct. 2021 by FlyBase; FBrf0222196]
Moderate- to high-scoring ortholog of human PARD3 and PARD3B (1 Drosophila to 2 human). Dmel\baz shares 22-26% identity and 34-38% similarity with the human genes.
High-scoring ortholog of human CDC42 (1 Drosophila to 1 human). Dmel\Cdc42 shares 92% identity and 95% similarity with the human gene.
Moderate- to high-scoring ortholog of human PRKCI and PRKCZ (1 Drosophila to 2 human). Dmel\aPKC shares 60-63% identity and 70-74% similarity with the human genes.
High-scoring ortholog of human PARD6A, PARD6B, and PARD6G (1 Drosophila to 3 human). Dmel\par-6 shares 48-55% identity and 62-73% similarity with the human genes.