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Molecular mechanisms of RET activation in human cancer
Massimo Santoro1, Rosa Marina Melillo, Francesca Carlomagno
1Centro di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltá di Medicina e Chirurgia, Universitá di Napoli Federico II, 80131 Naples, Italy.
Abstract:
Mutations that produce oncogenes with dominant gain of function target receptor protein tyrosine kinases (PTKs) in cancer and confer uncontrolled proliferation, impaired differentiation, or unrestrained survival to the cancer cell. However, insufficient PTK signaling may be responsible for developmental diseases. Gain of function of the RET receptor PTK is associated with human cancer. At the germline level, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and FMTC). Mutations of extracellular cysteines are found in MEN2A patients, and a Met918Thr mutation is responsible for most MEN2B cases. At the somatic level, gene rearrangements juxtaposing the tyrosine kinase domain of RET to heterologous gene partners are found in papillary carcinomas of the thyroid. These rearrangements generate the chimeric RET/PTC oncogenes. Both MEN2 mutations and PTC gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, the RET downstream signaling events. A multidocking site of the C-tail of RET is essential for both mitogenic and survival RET signaling. Such a site is involved in the recruitment of several intracellular molecules, such as the Shc, FRS2, IRS1, Gab1/2, and Enigma. The different activating mutations not only potentiate the enzymatic activity of the RET kinase but also may alter qualitatively RET signaling properties by: (1) altering RET autophosphorylation (in the case of the MEN2B mutation), (2) modifying the subcellular distribution of the active kinase, and (3) providing the active kinase with a scaffold for novel protein-protein interactions (as in the case of RET/PTC oncoproteins). This review describes the molecular mechanisms by which the different genetic alterations cause the conversion of RET into a dominant transforming oncogene.
Insights
Gain of function mutations in the RET receptor tyrosine kinase (RTK) drive cancer by promoting cell proliferation and survival. These RET alterations, including germline and somatic mutations, convert RET into a dominant oncogene.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Receptor protein tyrosine kinases (PTKs) are crucial for cell signaling; dysregulation, particularly gain of function, is implicated in cancer.
- The RET receptor PTK is a key player, with its aberrant activation linked to both human cancers and developmental disorders.
Purpose of the Study:
- To elucidate the molecular mechanisms by which genetic alterations convert the RET proto-oncogene into a dominant transforming oncogene.
- To review how different RET mutations and rearrangements potentiate its tyrosine kinase activity and downstream signaling.
Main Methods:
- Review of existing literature on RET mutations in cancer and developmental diseases.
- Analysis of molecular mechanisms involving RET kinase activity, autophosphorylation, subcellular localization, and protein-protein interactions.
Main Results:
- Germline RET mutations (e.g., MEN2A, MEN2B) and somatic RET/PTC rearrangements in thyroid cancer lead to enhanced RET kinase activity.
- Activating RET mutations alter signaling by modifying autophosphorylation, subcellular distribution, and protein interactions via a C-tail multidocking site.
Conclusions:
- Genetic alterations in RET can transform it into a potent oncogene, driving uncontrolled cell growth and survival.
- Understanding these mechanisms is vital for developing targeted therapies for RET-driven cancers and related disorders.