Function
AKT1 is one of three closely related serine/threonine-protein kinases (AKT1, AKT2, and AKT3) collectively known as the AKT kinase. This kinase family plays a crucial role in regulating numerous cellular processes, including metabolism, proliferation, cell survival, growth, and angiogenesis. These functions are mediated through the phosphorylation of a diverse range of downstream substrates on serine and/or threonine residues. Over 100 potential substrate candidates have been reported, although isoform specificity has not been established for most of them. AKT is responsible for regulating glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at Ser-50 negatively modulates its phosphatase activity, preventing dephosphorylation of the insulin receptor and attenuating insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is essential for insulin-stimulated glucose transport. AKT also regulates glucose storage in the form of glycogen by phosphorylating GSK3A at Ser-21 and GSK3B at Ser-9, leading to inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also believed to be a mechanism driving cell proliferation. AKT further regulates cell survival through the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation at Ser-83 decreases MAP3K5 kinase activity stimulated by oxidative stress, thereby preventing apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at Ser-939 and Thr-1462, activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and activation of RPS6KB1. AKT participates in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), resulting in binding of 14-3-3 proteins and cytoplasmic localization. Notably, FOXO1 is phosphorylated at Thr-24, Ser-256, and Ser-319. FOXO3 and FOXO4 are phosphorylated at equivalent sites. AKT plays a significant role in regulating NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). Phosphorylation of CREB1 induces the binding of accessory proteins required for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates Ser-454 on ATP citrate lyase (ACLY), potentially regulating ACLY activity and fatty acid synthesis. It activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of Ser-273, resulting in reduced cyclic AMP levels and inhibition of lipolysis. AKT phosphorylates PIKFYVE at Ser-318, increasing PI(3)P-5 activity. Another substrate is the Rho GTPase-activating protein DLC1, and its phosphorylation is implicated in the regulation of cell proliferation and growth. AKT acts as a key modulator of the AKT-mTOR signaling pathway, controlling the tempo of newborn neuron integration during adult neurogenesis, including proper neuron positioning, dendritic development, and synapse formation. AKT signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin, and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. It is essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. AKT may be involved in regulating placental development. It phosphorylates STK4/MST1 at Thr-120 and Thr-387, leading to inhibition of its kinase activity, nuclear translocation, autophosphorylation, and ability to phosphorylate FOXO3. It also phosphorylates STK3/MST2 at Thr-117 and Thr-384, inhibiting its cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1, and nuclear translocation. AKT phosphorylates SRPK2, enhancing its kinase activity towards SRSF2 and ACIN1 and promoting its nuclear translocation. It phosphorylates RAF1 at Ser-259 and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. AKT phosphorylates KAT6A at Thr-369, and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. It phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility. AKT phosphorylates prohibitin (PHB), playing a crucial role in cell metabolism and proliferation. It phosphorylates CDKN1A, for which phosphorylation at Thr-145 induces its release from CDK2 and cytoplasmic relocalization. These recent findings suggest that the AKT1 isoform plays a more specific role in cell motility and proliferation. AKT phosphorylates CLK2, controlling cell survival to ionizing radiation. It phosphorylates PCK1 at Ser-90, reducing the binding affinity of PCK1 to oxaloacetate and transforming PCK1 into an atypical protein kinase activity using GTP as a donor. AKT also acts as an activator of TMEM175 potassium channel activity in response to growth factors. It forms the lysoK(GF) complex together with TMEM175 and promotes TMEM175 channel activation, independently of its protein kinase activity.