Oncogenic role of heterotrimeric G proteins

Mutations that constitutively activate the α chains of G(s) and G(i2) by inhibiting their intrinsic GTPase activity are present in human endocrine tumours. The gsp oncogene is mainly found in pituitary GH secreting tumours and thyroid hyperfunctioning adenomas, where it induces a constitutive activation of the adenylyl cyclase-cAMP pathway. In pituitary and thyroid cells, this signal leads to abnormal proliferation and a persistent activation of differentiated functions. The gip2 oncogene has been identified in tumours of the ovary and adrenal cortex. Although the mechanisms of the oncogenic action of mutationally activated α(i2) are less clear than those of α(s), the protein can induce transformation of certain cell types. At least five other α chains, which share with α(s) and α(i2) common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein βγ subunits clearly control signals involved in cell growth. So far, there is no evidence for mutations of these molecules in human tumours. Further studies will tell us whether at present we know of only two members of a much larger family of G protein oncogenes.