Oncogenic role of heterotrimeric G proteins.

Mutations that constitutively activate the alpha chains of Gs and Gi2 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 alpha i2 are less clear than those of alpha s, the protein can induce transformation of certain cell types. At least five other alpha chains, which share with alpha s and alpha i2 common structural and functional mechanisms of GTP hydrolysis, activate mitogenic pathways leading to transformation. In addition, the G protein beta gamma 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.