Multiple Endocrine Adenomatosis is commonly called Multiple Endocrine Neoplasia because it forms tumors. There are two subtypes to this disease: Type 1 and Type 2. Though the names are similar, they are quite different conditions.

MEN2 has an autosomal dominant pattern of inheritance. It results in multiple malignant and benign tumors in glands like the thyroid, parathyroid, and adrenals.

MEN2 has two subtypes: MEN2A and MEN2B. MEN2A has a high incidence of medullary carcinoma of the thyroid, whereas MEN2B has the same symptoms as MEN2A, but has thickening of the nerves and neuromas on the mucosal surface of mouth and lips. (IS THIS A SQUAMOUS CELL CARCINOMA?)

MEN2 results from a mutation on the RET proto-oncogene. The RET proto-oncogene that codes for a protein in the TGF-β (Transforming Growth Factor Beta) signal transduction pathway. A mutation on the RET gene resulting in a gain-of-function of the protein, results in a disturbance in the TGF-β signal transduction pathway, and this results in the carcinoma. Because the TGF-β signal transduction pathway occurs in multiple locations in the endocrine system, and in organs with endocrine-like function, the carcinoma occurs in multiple locations in the body.

When the RET gene is mutated in a way that causes a loss-of-function variant, the result is Hirschsprung Disease.

The TGF-β is a protein that controls proliferation, cellular differentiation, and other functions in most cells.

In normal cells, TGF-β, acting through its signalling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, the TGF-β no longer controls the cell, and the cell cycle continues unregulated from the G1 phase to the S phase.

The RET gene also codes for the receptor tyrosine kinase for glial-cell-line derived growth factor (gdnf) and neurturin.

Conformation change in the receptor activates an intrinsic kinase activity that phosphorylates other cellular proteins.

The TGF-β protein is essential for the normal development of several kinds of nerve cells, including nerves in the intesting (enteric neurons) and the portion of the nervous system that controls involuntary body functions such as the heart rate (autonomic nervous system).

MEN2A and MEN2B mutations are specific point mutations that activate the receptor and cause it to phosphorylate tyrosine even in the absence of gdnf or neurturin.

The mutation that causes a gain-of-function for MEN2A is cys634arg.

The mutation that causes a gain-of-function for MEN2B is met918thr.

- The RET protooncogene is one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation. The RET gene was defined as an oncogene by a classical transfection assay. RET can undergo oncogenic activity in vivo and in vitro by cytogenic rearrangement. Mutations in the RET gene are associated with multiple endocrine neoplasia type IIA, multiple endocrine neoplasia type IIB, Hirschsprung Disease, and medullary thyroid carcinoma.