PTEN Signaling

PTEN is a phosphatase whose catalytic domain is frequently inactivated by somatic mutations in a variety of human cancers including prostate, breast, brain, and kidney cancers. PTEN is a tumor suppressor protein that functions both as a dual specificity protein phosphatase and an inositol phospholipid phosphatase, and regulates signaling pathways involved in cell growth, migration, and apoptosis.Phosphorylation of PTEN by CK2 decreases its proteasome-mediated degradation and regulates its function. Unphosphorylated PTEN strongly associates with MAGI-2. This interaction enhances the dephosphorylation of phosphatidylinositol 3,4,5-triphosphate (PIP3), thus antagonizing the downstream functions mediated by the phosphoinositide 3-kinase (PI3K), such as activation of AKT and its downstream effectors (IKK, p70S6K, FOXO, BAD, Caspase 9, and GSK3), cell survival, and cell proliferation. Loss of PTEN results in elevated levels of PIP3 and the subsequent phosphorylation and activation of AKT by PDK1 and ILK. Therefore loss of PTEN prevents cells from undergoing apoptosis by inhibiting the proapoptotic protein BAD, the cell death pathway protein Caspase 9, as well as inhibiting the nuclear translocation of the transcription factor FOXO, which induces apoptosis through regulation of FasL, BIM, p27Kip1, and p21Cip1.Furthermore, PTEN suppresses cell migration and spreading by two different mechanisms: 1. inhibition of the FAK-CAS signaling cascade, through direct dephosphorylation and inhibition of FAK. 2. inhibition of the Ras-Raf-MAPK signaling cascade, through inhibition of integrin- or growth factor-induced SHC phosphorylation and thus suppression of the association of SHC with GRB2.Through regulation of PIP3 levels, AKT and FAK activation, and SHC recruitment, PTEN is involved in cell growth, migration, and survival. On the other hand, loss of PTEN contributes to cell transformation and neoplastic growth.