| Annotation topic | Summary for rat AKT1 (UniProt P47196) | Key evidence |
|---|---|---|
| Identity verification | The target matches **Rattus norvegicus Akt1**, encoding **RAC-alpha serine/threonine-protein kinase / PKBα**. A 2024 rat study explicitly states that the **Rattus norvegicus Akt-1 structure** used for docking was retrieved from UniProt as **P47196**, confirming the accession-gene-organism mapping. Core AKT1 architecture and regulation are consistent with canonical mammalian AKT1/PKBα literature. | (pqac-00000024, pqac-00000000) |
| Domains | AKT1 has the canonical AKT layout: **N-terminal PH domain**, **central bilobal kinase domain**, and **C-terminal hydrophobic/regulatory tail (hydrophobic motif)**. This organization underlies phosphoinositide sensing, catalytic phosphorylation, and C-tail-dependent regulation. | (pqac-00000002, pqac-00000003, pqac-00000015) |
| Catalytic activity (EC 2.7.11.1) | AKT1 is an **AGC-family serine/threonine protein kinase** that transfers phosphate from ATP to **Ser/Thr residues on protein substrates**. Its kinase activity is central to growth, survival, metabolism, and anabolic signaling. Representative downstream substrates include **GSK3** and **FOXO** proteins. | (pqac-00000000, pqac-00000014, pqac-00000008) |
| Activation mechanism | Activation is membrane- and phosphorylation-coupled. The PH domain binds **PI(3,4,5)P3 (PIP3)** and **PI(3,4)P2**, recruiting AKT1 to phosphoinositide-enriched membranes. **PDK1 phosphorylates Thr308** in the activation loop for partial activation; **mTORC2 phosphorylates Ser473** in the hydrophobic motif for full activation/substrate tuning. **Thr450** turn-motif phosphorylation contributes to folding/stability. | (pqac-00000015, pqac-00000012, pqac-00000001) |
| Autoinhibition | In unstimulated cells, AKT1 adopts a **PH-in autoinhibited conformation** in which a **PH–kinase domain interface** masks the active state and sequesters the lipid-binding site. Structural work showed that phosphorylation alone does not fully relieve this state; productive activation requires **both phosphoinositide binding and regulatory phosphorylation**. | (pqac-00000009, pqac-00000010, pqac-00000013) |
| Localization / compartments | AKT1 is largely **cytosolic (and can be nuclear) in quiescent cells**, but active signaling is concentrated at **membrane-associated compartments**, especially the **plasma membrane** and, in some models, **endosomal membranes**. Lipid identity helps specify compartmental signaling, and dissociation from membranes promotes rapid inactivation. | (pqac-00000027, pqac-00000028, pqac-00000030) |
| Termination / negative regulation | AKT signaling is terminated at two levels: **PTEN** removes the lipid signal by dephosphorylating **PIP3 to PI(4,5)P2**, preventing membrane recruitment; **PP2A** and **PHLPP** dephosphorylate AKT at key regulatory residues, especially after membrane dissociation. This couples localization, phosphorylation state, and signaling duration. | (pqac-00000031, pqac-00000027, pqac-00000028) |
| Representative substrates / pathway effects | Activated AKT1 phosphorylates substrates including **GSK3** and **FOXO1/3a**, thereby promoting cell survival, proliferation, metabolism, and anabolic growth programs. Phosphorylation state, especially the **Thr308/Ser473 balance**, can influence substrate preference and signaling output. | (pqac-00000014, pqac-00000011, pqac-00000000) |
| 2023–2024 clinical translation | A major recent milestone was **capivasertib** clinical translation. In **CAPItello-291**, capivasertib + fulvestrant improved **median PFS from 3.6 to 7.2 months overall (HR 0.60)** and from **3.1 to 7.3 months** in pathway-altered tumors; reviews note FDA approval in HR+/HER2− advanced breast cancer with **PIK3CA/AKT/PTEN** alterations. Earlier supportive phase II data (FAKTION) showed **PFS 10.3 vs 4.8 months** and **OS 29.3 vs 23.4 months**. | (pqac-00000019, pqac-00000036, pqac-00000023) |
| Clinical trial registry implementation | **NCT04305496 (CAPItello-291)**: phase III, randomized, double-blind capivasertib + fulvestrant vs placebo + fulvestrant; **enrollment 818**; capivasertib **400 mg BID**, **4 days on/3 days off**; primary endpoint **PFS** in overall and altered populations. **NCT07281833 (CAPIcorn)**: phase III implementation-oriented study; plans to **screen ~600** and enroll **250**, enriching for **PIK3CA/AKT1/PTEN** alterations; evaluates treatment plus patient-reported-outcome adherence metrics. | (pqac-00000038, pqac-00000037, pqac-00000040) |
| 2023 AKT1-specific experimental study | In a 2023 TNBC brain-metastasis model, **ipatasertib** reduced viability and radiosensitized MDA-MB-231BR cells, but **AKT1 knockout** showed mixed/complex isoform-specific biology: reduced viability in one clone yet **increased migration and clonogenic survival** in both KO clones with decreased radiosensitivity, highlighting that AKT1 loss is not functionally equivalent to pan-AKT inhibition. The paper notes PI3K/AKT pathway activation in **43–70% of breast cancers**. | (pqac-00000021) |


*Table: This table summarizes verified identity, molecular function, regulation, localization, and recent translational evidence for rat AKT1/PKBα (UniProt P47196). It is designed as a compact functional-annotation reference with citations to the available evidence contexts.*