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Definition: How does the PI3K-Akt pathway mediate cellular response to hormones?

The PI3K-Akt pathway is a signaling pathway that plays a crucial role in mediating cellular response to hormones. It is activated by various hormones, such as insulin and growth factors, and regulates important cellular processes including cell growth, proliferation, survival, and metabolism.

Activation of the PI3K-Akt Pathway

The activation of the PI3K-Akt pathway begins with the binding of hormones to their respective cell surface receptors. This binding triggers a series of events that ultimately lead to the activation of phosphoinositide 3-kinase (PI3K), an enzyme that phosphorylates phosphatidylinositol lipids in the cell membrane.

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Once activated, PI3K generates phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 serves as a docking site for Akt (also known as protein kinase B), a serine/threonine kinase that plays a central role in the PI3K-Akt pathway.

Activation of Akt and Cellular Response

Upon recruitment to the cell membrane, Akt is phosphorylated at two critical sites: threonine 308 (Thr308) and serine 473 (Ser473). Phosphorylation at Thr308 is mediated by phosphoinositide-dependent kinase 1 (PDK1), while phosphorylation at Ser473 is mediated by the mammalian target of rapamycin complex 2 (mTORC2).

Once fully activated, Akt phosphorylates a wide range of downstream targets, including transcription factors, kinases, and other signaling molecules. These phosphorylation events regulate various cellular processes, such as protein synthesis, glucose metabolism, cell cycle progression, and cell survival.

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One of the key mechanisms by which the PI3K-Akt pathway mediates cellular response to hormones is through the activation of the mammalian target of rapamycin complex 1 (mTORC1). Akt phosphorylates and inhibits the tuberous sclerosis complex 2 (TSC2), leading to the activation of mTORC1. mTORC1, in turn, promotes protein synthesis and cell growth.

Additionally, the PI3K-Akt pathway regulates the activity of several transcription factors, including forkhead box O (FoxO) proteins. Akt phosphorylates FoxO proteins, leading to their exclusion from the nucleus and subsequent inhibition of their transcriptional activity. This regulation plays a crucial role in cell survival and apoptosis.

In summary, the PI3K-Akt pathway mediates cellular response to hormones by activating Akt, which phosphorylates and regulates various downstream targets involved in cell growth, proliferation, survival, and metabolism. This pathway plays a critical role in normal cellular function and its dysregulation has been implicated in various diseases, including cancer, diabetes, and cardiovascular disorders.

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