[Frontiers in Bioscience 16, 422-439, January 1, 2011]

A minireview: the role of MAPK/ERK and PI3K/Akt pathways in thyroid follicular cell-derived neoplasm

Ewa Brzezianska1, Dorota Pastuszak-Lewandoska1

1Department of Molecular Bases of Medicine, Medical University of Lodz, Pomorska St. 251, 92-213 Lodz, Poland

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. RAS/RAF/MEK/ERK signaling pathway
3.1. Aberrant signaling through the RAS/RAF/MEK/ERK pathway in thyroid tumorigenesis
3.1.1. The role of RET/PTC rearrangements
3.1.2. The role of TRK rearrangements
3.1.3. The role of Ras protein and RAS mutation
3.1.4. The role of B-Raf kinase and BRAF mutation
3.2. RET/PTC, RAS, BRAF in RAS/RAF/MEK/ERK pathway and their influence on gene expression profiles in thyroid neoplasms
4. PI3K/Akt signaling pathway and its role in malignant transformation
4.1. Aberrant signaling of PI3K/Akt pathway in thyroid tumorigenesis
4.1.1. The role of PIK3CA alterations
4.1.2. The role of AKT alterations
4.1.3. The role of PTEN alterations
5. Interactions between RAS/RAF/MEK/ERK alterations and PI3K/Akt pathway activation
6. Acknowledgements
7. References

1. ABSTRACT

The MAPK/ERK (mitogen - activated protein kinase/extracellular signal-regulated kinase signaling pathway) and PI3K/Akt (lipid kinase phoshoinositide-3-kinase signaling pathway) play an important role in transmission of cell signals through transduction systems (ligands, transmembrane receptors and cytoplasmic secondary messengers) to cell nucleus, where they influence the expression of genes that regulate important cellular processes: cell growth, proliferation and apoptosis. The genes, coding the signaling cascade proteins (e.g., RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cell. Genetic and epigenetic alternations, concerning MAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction in consequence of malignant follicular cell transformation. This review is focused mainly on genetic alterations in genes, coding signaling pathway proteins. Moreover, it is additionally pointed out that genetic, as well as epigenetic DNA changing via aberrant methylation of several tumour suppressor and thyroid-specific genes are associated with tumour aggressiveness, being a jointly responsible mechanism for thyroid tumorigenesis. The understanding of this molecular mechanism provides access to novel molecular therapeutic strategies for inhibiting oncogenic activity of signaling pathways.