Endocrine Abstracts

Mitogen-activated protein kinases (MAPK) are a family of serine/threonine kinases and are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated protein kinases (ERK1 and 2); c-Jun N-terminal kinases (JNK1-3); p38s (α, β, γ, δ) and ERK5. Aberrant regulation of MAPK cascades contribute to cancer and other human diseases. In particular, ERK 1/2 which is a downstream component of a signaling module that is activated by the Raf serine/threonine kinases has been the subject of intense research. Raf activates the MAPK kinase (MEK1/2) dual-specificity protein kinases, which then activate ERK1/2. The mutational activation of Raf in human cancers supports the importtant role of this pathway in human oncogenesis. Additionally, the Raf-MEK-ERK pathway is a key downstream effector of the Ras small GTPase, the most frequently mutated oncogene in human cancers.

The serine/threonine protein kinase PKB/Akt is a crucial regulator of cell growth, proliferation, differentiation and apoptosis. Mitogenic signaling by receptor tyrosine kinases that increase phosphatidylinositol 3-kinase (PI3K) activity lead to activation of PKB/Akt which in turn triggers a number of responses like cell growth, survival and increased motility. Interactions between MAPK and PI3K/Akt pathways have also been reported (1).

There are a number of studies investigating the role of these signaling cascades in pituitary tumorigenesis. In somatolactotroph GH4C1 cell lines, both gsp oncogene and over-expression of wild-type G_sα protein was found to initiate a sustained MAPK ERK 1/2 activation (2). In a study performed in GH-secreting adenomas and non-functioning pituitary adenomas, the activation of G-protein-coupled receptors by neurohormones caused an increase in ERK 1/2 activity, while increasing cAMP by forskolin increased ERK 1/2 activity only in GH-omas (3). In a study by Muşat et al. Akt mRNA was found to be over-expressed and immunohistochemical expression of phosho-Akt was found to be higher in pituitary adenomas compared to normal pituitaries (4). In a knock-in mutant mouse model carrying a mutation in thyroid hormone receptor-β gene, spontaneous development of TSH-omas with accompanying activation of Akt and its downstream effectors were noted (5). In a recent study, mutations and amplifications in PI3K3CA gene of the PI3K/Akt pathway have been found in invasive pituitary tumors compared to noninvasive ones (6).

In conclusion, there are reports showing both MAPK and PI3K/Akt over-activation in pituitary tumors, however whether activation of these pathways are primary events or their activation results from upstream regulators of these pathways needs to be revealed.