JAK/STAT pathway dysregulation in tumors: a Drosophila perspective

Abstract

Sustained activation of the JAK/STAT pathway is causal to human cancers. This pathway is less complex in Drosophila, and its dysregulation has been linked to several tumor models in this organism. Here, we discuss models of metastatic epithelial and hematopoietic tumors that are causally linked to dysregulation of JAK/STAT signaling in Drosophila. First, we focus on cancer models in imaginal discs where ectopic expression of the JAK/STAT pathway ligand Unpaired downstream of distinct tumor suppressors has emerged as an unexpected mediator of neoplastic transformation. We also discuss the collaboration between STAT and oncogenic Ras in epithelial transformation. Second, we examine hematopoietic tumors, where mutations that cause hyperactive JAK/STAT signaling are necessary and sufficient for "fly leukemia". We highlight the important contributions that genetic screens in Drosophila have made to understanding the JAK/STAT pathway, its developmental roles, and how its function is co-opted during tumorigenesis.

Keywords: Carcinoma; Chinmo; Dome; ESCRT; Hop; Imaginal discs; JAK/STAT; Melanotic tumors; Myeloproliferative neoplasms; Notch; PRC1; Ras; Scribbled; Socs36E; Stat92E; T42; Tum-l; Upd; dPIAS.

Fig. 1. The Drosophila JAK/STAT pathway

(A) The Drosophila JAK-STAT pathway consists of three Upd ligands collectively referred to as Upd (green). Upd activates the receptor Dome (brown), which results in activation of Hop (orange), leading to tyrosine phosphorylation (brown circles) on Dome. Stat92E dimers (blue) bind to the phosphorylated receptor. Once bound, Stat92E is phosphorylated on tyrosine 711, generating an active Stat92E dimer that undergoes nuclear translocation, where it binds to a consensus TTCNNNGAA site and alters gene expression. Socs36E is a Stat92E target gene that encodes a negative regulator (magenta) of Dome/JAK activity. A second receptor ET/Lat (red) inhibits JAK/STAT signaling. dPIAS (gray) inhibits activated Stat92E dimers. (B) Domain structure of Hop. Hop contains a bona fide tyrosine kinase domain (JH1, yellow), a pseudokinase domain that lacks kinase activity (JH2, green), an atypical SH2 domain (magenta), and a FERM domain (blue) that mediates attachment to cytokine receptors. In the wild type Hop protein, the JH2 domain prevents the activation of the kinase domain, JH1 (top arrow). The E695K (T42) or G341E (Tum-l) mutations lead to activation (bottom arrows) of JH1.

Fig. 2. JAK/STAT signaling in eye development and imaginal disc-derived tumors

(A,B) Scanning electron micrograph of a wild type (A) or GMR-upd (B) adult eye. Note the dramatic overgrowth in B. (C) Model of regulation of JAK/STAT pathway signaling in the developing eye imaginal disc. Notch signaling (N^act) induces upd in cells at the posterior midline (blue area). Upd activates Dome and Stat92E (labelled STAT^P) in adjacent cells. PRC1 normally repress upd expression, while JNK signaling can induce it. ESCRT components normally restrict Notch and Dome activity, while Csk represses Stat92E activity. In addition, early in eye development, Upd can act upstream of Notch and induce Notch activity at the midline (green arrow). Activated Stat92E (STAT^P) also restricts Notch activity by repressing expression of Ser, which encodes a Notch ligand. (D) Model of regulation of JAK/STAT pathway signaling by ESCRT components. Active Notch (magenta) and Dome (brown) receptors are trafficked into endosomes, where they can induce target genes like upd (green) and crb (blue), respectively. ESCRT factors promote the trafficking of Notch and Dome into the lysosome for degradation. In ESCRT mutants, Notch and Dome are trapped in an activated state in endosomes, where their unbridled activity causes cell cycle deregulation and transformation. (E) Model of metastatic tumors caused by gain of Ras^V12 and loss of scrib in the eye disc. In wild type epithelial cells (gray), Scrib repressed JNK activity. In a cell that has Ras^V12 and lacks scrib (yellow), JNK signaling is now activated and upd genes are ectopically expressed (green). The ectopic Upd protein (green) leads to autocrine and paracrine (not depicted) activation of Dome (brown) and Stat92E (blue). The autonomous collaboration of Ras^V12 and activated Stat92E causes neoplastic transformation and metastasis.

Fig. 3. JAK/STAT signaling in hematopoiesis and melanotic tumors

(A) The lymph gland is the larval hematopoietic organ. In the anterior lobe, there are three zones. Cells in the posterior signaling center (PSC, magenta) form the niche for multipotent progenitors called prohemocytes that reside in the medullary zone (MZ, yellow). Prohemocytes give rise to all Drosophila blood lineages, plasmatocytes, crystal cells and lamellocytes. Differentiation of hemocytes occurs in the cortical zone (CZ, orange). (B) Model of Stat92E dimer activity (blue) and gene regulation downstream of Hop^Tum-l. See text for details. (C,D) Micrograph of a wild type larva (C) or a hop^Tum-l larva (D) reared at the restrictive temperature of 29°C. There is a large melanotic tumor in the abdomen of the hop^Tum-l larva (D, arrowhead) but none in the wild type control (C).