AKT Signaling Pathway: Regulation by the Insulin Signaling Cascade

Summary

This lesson covers the insulin signaling pathway, focusing on its regulation of the Akt pathway. Insulin binding to the insulin receptor triggers a cascade of phosphorylation events that activate key molecules like IRS-1/2, PI3K, and Akt. The pathway regulates glucose uptake by activating GLUT4 vesicles and involves complex feedback loops, including inhibition of the mTOR pathway, which turns off the insulin signaling to prevent overstimulation. Key phosphorylation sites on Akt (Threonine 308 and Serine 473) are essential for its activation, and the lesson emphasizes the roles of PDK1 and mTOR complex 2 in regulating this pathway.

Takeaways

• 😀 Insulin binds to the insulin receptor on a cell, initiating auto-phosphorylation and activation of insulin receptor substrates (IRS 1 and 2).
• 😀 P10 inhibits two steps in the insulin signaling pathway, dephosphorylating both IRS 1 and 2 and phosphatidylinositol (PIP) 3.
• 😀 When IRS 1 and 2 are phosphorylated, they recruit P85 and PI3K, activating PI3K to convert PIP2 into PIP3.
• 😀 P10 regulates the insulin signaling pathway by dephosphorylating PIP3 back to PIP2.
• 😀 Elevated levels of PIP3 recruit pyruvate dehydrogenase kinase 1 (PDK1) and Akt to the cell membrane, where PDK1 phosphorylates Akt at threonine 308.
• 😀 mTOR complex 2 (mTORC2) phosphorylates Akt at serine 473, which is an essential activation site for Akt.
• 😀 Protein phosphatase 2A (PP2A) dephosphorylates Akt at threonine 308, and PHLP1 dephosphorylates Akt at serine 473, creating counter-regulatory mechanisms.
• 😀 Akt activation leads to the translocation of vesicles containing glucose transporter (GLUT4) to the cell membrane, promoting glucose uptake and glycolysis.
• 😀 The Akt pathway, through phosphorylation, regulates glucose uptake by inhibiting AS160, which otherwise blocks GLUT4 vesicle translocation.
• 😀 Akt regulates mTOR complex 1 (mTORC1), activating it by inhibiting TSC2, which normally keeps mTORC1 inactive, promoting cell growth and protein synthesis.
• 😀 mTORC1 activation leads to feedback inhibition of the insulin signaling pathway by phosphorylating IRS 1 and 2, ultimately turning off the pathway.

Q & A

What happens when insulin binds to the insulin receptor on a cell?

When insulin binds to the insulin receptor on a cell, it triggers an auto-phosphorylation mechanism on the insulin receptor, which then leads to the phosphorylation of insulin receptor substrates (IRS-1 and IRS-2).

How does P10 regulate the insulin signaling pathway?

P10 negatively regulates the insulin signaling pathway by dephosphorylating IRS-1 and IRS-2, as well as PIP3, converting it back to PIP2.

What role does PI3K play in the insulin signaling pathway?

PI3K is recruited by phosphorylated IRS-1 and IRS-2. It catalyzes the conversion of PIP2 to PIP3, which accumulates within the cell and plays a key role in Akt activation.

What is the significance of PDK1 in Akt activation?

PDK1 is critical for Akt activation as it phosphorylates Akt at threonine 308, which is an essential phosphorylation site for Akt's full activation.

How does mTORC2 contribute to Akt activation?

mTORC2 activates Akt by phosphorylating it at serine 473, another key phosphorylation site that completes Akt's activation process.

What are the functions of PHLPP and PP2A in regulating Akt?

PHLPP dephosphorylates Akt at serine 473, while PP2A dephosphorylates Akt at threonine 308. These phosphatases help regulate the balance of Akt activation and deactivation.

How does Akt facilitate glucose uptake into the cell?

Akt facilitates glucose uptake by phosphorylating and inhibiting AS160, which is an inhibitor of GLUT4 vesicle translocation. This allows GLUT4 to move to the cell membrane, enabling glucose to enter the cell.

What role does Akt play in regulating the mTORC1 pathway?

Akt regulates mTORC1 by inhibiting TSC2, a negative regulator of mTORC1. This inhibition activates mTORC1, leading to the phosphorylation of downstream targets such as p70 S6K.

What is the negative feedback regulation in the insulin signaling pathway?

The negative feedback regulation occurs when mTORC1, after being activated by Akt, phosphorylates IRS-1 and IRS-2, which inhibits further activation of the insulin signaling pathway, essentially turning it off.

What are the key phosphorylation sites on Akt and their significance?

The key phosphorylation sites on Akt are threonine 308, which is phosphorylated by PDK1, and serine 473, which is phosphorylated by mTORC2. These phosphorylation events are essential for Akt activation and its downstream effects.