Rabaptin-5 and Rabex-5 are neoplastic tumour suppressor genes that interact to modulate Rab5 dynamics in Drosophila
1MRC Centre for Developmental and Biomedical Genetics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Abstract:
Endocytosis plays an important role in the regulation of tumour growth and metastasis. In Drosophila, a number of endocytic neoplastic tumour suppressor genes have been identified that when mutated cause epithelial disruption and over-proliferation. Here we characterise the Drosophila homologue of the Rab5 effector Rabaptin-5, and show that it is a novel neoplastic tumour suppressor. Its ability to bind Rab5 and modulate early endosomal dynamics is conserved in Drosophila, as is its interaction with the Rab5 GEF Rabex5, for which we also demonstrate neoplastic tumour suppressor characteristics. Surprisingly, we do not observe disruption of apico-basal polarity in Rabaptin-5 and Rabex-5 mutant tissues; instead the tumour phenotype is associated with upregulation of Jun N-terminal Kinase (JNK) and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signalling.
Insights
Rabaptin-5 and Rabex-5 act as novel neoplastic tumor suppressors in Drosophila. Their mutations disrupt tumor growth and metastasis by upregulating Jun N-terminal Kinase (JNK) and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathways.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Endocytosis is crucial for regulating tumor growth and metastasis.
- Mutations in endocytic genes in Drosophila can lead to epithelial disruption and over-proliferation, indicating their role as tumor suppressors.
Purpose of the Study:
- To characterize the Drosophila homologue of Rab5 effector Rabaptin-5 as a novel neoplastic tumor suppressor.
- To investigate the role of Rabex5, a Rab5 Guanine nucleotide Exchange Factor (GEF), in tumor suppression.
Main Methods:
- Characterization of Rabaptin-5 and Rabex-5 in Drosophila models.
- Analysis of endosomal dynamics and protein interactions (Rab5, Rabex5).
- Assessment of signaling pathways, including Jun N-terminal Kinase (JNK) and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathways.
Main Results:
- Rabaptin-5 functions as a novel neoplastic tumor suppressor in Drosophila.
- The interaction of Rabaptin-5 with Rab5 and its modulation of early endosomal dynamics are conserved.
- Rabex5 also exhibits neoplastic tumor suppressor characteristics.
- Tumor phenotypes in Rabaptin-5 and Rabex-5 mutants are linked to the upregulation of JNK and JAK/STAT signaling, rather than apico-basal polarity disruption.
Conclusions:
- Rabaptin-5 and Rabex-5 are novel neoplastic tumor suppressors in Drosophila.
- Their tumor suppressor functions are mediated through the regulation of JNK and JAK/STAT signaling pathways.
- These findings offer new insights into the genetic regulation of tumor growth and metastasis via endocytic pathways.
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