PHLPP

PHLPPs, "PH domain and leucine rich repeat protein phosphatase," refers to a pair of protein phosphatases, PHLPP1 and PHLPP2, which are important regulators of Akt serine-threonine kinases (Akt1, Akt2, Akt3).

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PHLPP dephosphorylates the Serine473 site in Akt, thus inactivating the kinase.

PHLPP Protein phosphatases control the amount of phosphorylated Akt

The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms, at one of the two critical phosphorylation sites required for activation: Serine473. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt2 and Akt3.

AKT family: AKT1, AKT2, AKT3

In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1).

Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.

Akt2 is an important signaling molecule in the Insulin signaling pathway. It's required to induce glucose transport.

These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway ^[1].

The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains ^[2].

Phosphorylation of Akt by PDK1 and PDK2

Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDK1) and PDK2. First, the mammalian target of rapamycin complex 2 (mTORC2) phosphorylates Akt at Serine473; mTORC2 therefore functionally acts as the long-sought PDK2 molecule. Phosphorylation by PDK2 stimulates the subsequent phosphorylation of Akt at Threonine308 by PDK1. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the Akt signaling pathway. The PHLPPs therefore antagonize PDK1 and PDK2, since they dephosphorylate the site that PDK1 phosphorylates.