phosphorylated at position T450 in the turn motif when Akt1 is translated. If Akt1 is not phosphorylated at this position, Akt1 does not fold in the right way. The T450-non-phosphorylated misfolded Akt1 is ubiquitinated and degraded by the proteasome. Akt1 is also phosphorylated at T308 and S473 during IGF-1 response, and the resulting polyphosphorylated Akt is ubiquitinated partly by E3 ligase NEDD4. Most of the ubiquitinated-phosphorylated-Akt1 is degraded by the proteasome, while a small amount of phosphorylated-Akt1 translocates to the nucleus in a ubiquitination-dependent way to phosphorylate its substrate. A cancer-derived mutant Akt1 (E17K) is more readily ubiquitinated and phosphorylated than the wild type Akt1. The ubiquitinated-phosphorylated-Akt1 (E17K) translocates more efficiently to the nucleus than the wild type Akt1. This mechanism may contribute to E17K-Akt1-induced cancer in humans. Lipid phosphatases and PIP3 PI3K-dependent Akt1 activation can be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above. PTEN acts as a phosphatase to dephosphorylate PIP3 back to PIP2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt1 activation decreases significantly, as do all of the downstream pathways that depend on Akt1 for activation. PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1 and SHIP2. These poly-phosphate inositol phosphatases dephosphorylate PIP3 to form PIP2. Protein phosphatases The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt2 and Akt3. Function The Akt kinases regulate cellular survival and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins, master lysosomal regulator TFEB and murine double minute 2 (MDM2). Cell survival Akt kinases can promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the Bcl-2 family. Akt1 can phosphorylate BAD on Ser136, which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function. Akt1 can also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes. Cell cycle The Akt isoforms are known to play a role in the cell cycle. Under various circumstances, activation of Akt1 was shown to overcome cell cycle arrest in G1 and G2 phases. Moreover, activated Akt1 may enable proliferation and survival of cells that have sustained a potentially