H2020Индивидуална стипендия2018–2020

REMIX · Effects of rewiring microexons (REMIX) on tissue-specific signaling networks

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-03-01 → 2020-06-20
Финансиране от ЕС: 170 122 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Микроекзоните регулират работата на протеините кинази, като променят начина, по който те взаимодействат помежду си в различните тъкани. Разбирането на тези процеси помага да се разбере как промените в РНК молекулите стимулират растежа на туморите.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Effects of rewiring microexons (REMIX) on tissue-specific signaling networks

Alternative splicing of messenger RNA in different tissues of the body allows custom-tailoring the function of a given gene to its environment. This mechanism of increasing genetic diversity is also frequently hijacked by tumors to improve evolutionary fitness, by selecting for splice variants that provide a growth and/or survival advantage to the cell. For example, signaling pathways that promote inappropriate proliferative activity can be upregulated through the selective use of isoforms with increased activity. In this MSC action, we focused on a specific type of alternative splicing called microexon splicing, and we aimed to understand the role it plays in regulating the activity of kinases, one of the key effectors of oncogenic signaling pathways. By calculating a tissue-specificity score for all kinase microexons, we determined that microexons outside of the catalytic kinase domain are significantly more likely to display alternative splicing patterns across different tissues than those within the kinase domain, which generally display constitutive splicing patterns. This finding suggests that microexons in kinases serve to modulate their interactions with other proteins, rather than altering their catalytic activity or substrate specificity at the peptide level. Analysis of transcriptomic data from The Cancer Genome Atlas revealed a global downregulation of microexon inclusion in tumors, driven by hypersilencing of the microexon splicing factor SRRM4. This discovery revealed a previously uncovered antiproliferative role for microexons and SRRM4 in non-neural tissues, adding a new element to the overall picture of splicing dysregulation in cancer. These findings are important for society as they help reveal how changes to RNA molecules promote tumor growth, which is important for identifying novel cancer treatment strategies.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Signaling networks control a vast range of complex cellular behaviors. The wiring of these networks varies greatly from one cell type to another in the body, depending on the specific functions required of different tissues. However, the mechanisms controlling the tissue-specific wiring of signaling networks are poorly understood. Kinases play a major role in directing signal flow by interacting with and phosphorylating specific target proteins. Interestingly, recent studies on the tissue-specific alternative splicing of very small exons called microexons found an enrichment of these microexons in kinases. This raised the question of whether microexons might occur in regions of kinases mediating specific kinase-substrate interactions. Theoretically, such “rewiring microexons” could contribute to the differential regulation of signaling networks in different cellular contexts. Furthermore, their dysregulation could potentially lead to pathogenic signaling in diseases such as cancer.Accordingly, the proposed research will address the questions: What role do microexons play in regulating kinase substrate specificity and tissue-specific wiring of signaling networks, and what are their potential roles in cancer cell signaling? To answer these questions, I will (1) experimentally determine the substrate specificities of kinases with/without microexons, (2)demonstrate the ability of the candidate microexons to rewire cellular signaling networks, and (3) investigate the dysregulation of kinase microexons in cancer using bioinformatics. This multidisciplinary study will fill a gap in our understanding of the functional roles of microexons in regulating kinase substrate specificity, and help to unravel the mechanisms underlying the immense variation of signaling activities between different cell types both in health and disease.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACIO CENTRE DE REGULACIO GENOMICA · BarcelonaКоординаторИспания