Extracellular signals are usually required for animal cells to grow and divide, as well as to survive .
Members of the insulinlike growth factor (IGF) family of signal proteins, for example, RTKs stimulate many types of animal cells to survive and grow.
1.They bind to specific RTKs which activate PI 3-kinase to produce PI(3,4,5)P3.
2.The PI(3,4,5)P3 recruits two protein kinases to the plasma membrane via their PH domains—
a. Akt (also called protein kinase B, or PKB)
b. Phosphoinositide-dependent protein kinase 1 (PDK1), and this leads to the activation of Akt ).
3. Once activated, Akt phosphorylates various target proteins at the plasma membrane, as well as in the cytosol and nucleus.
4.Actions of Akt all conspire to enhance cell survival and growth.
The control of cell growth by the PI-3-kinase–Akt pathway depends in part on a large protein kinase called TOR (named as the target of rapamycin, a bacterial toxin that inactivates the kinase and is used clinically as both an immunosuppressant and anticancer drug).
TOR was originally identified in yeasts in genetic screens for rapamycin resistance; in mammalian cells, it is called mTOR, which exists in cells in two functionally distinct multiprotein complexes.
1. mTOR complex 1- Contains the protein raptor; this complex is sensitive to rapamycin, and it stimulates cell growth—both by promoting ribosome production and protein synthesis and by inhibiting protein degradation.
Complex 1 also promotes both cell growth and cell survival by stimulating nutrient uptake and metabolism. The mTOR in complex 1 integrates inputs from various sources, including extracellular signal proteins referred to as growth factors and nutrients such as amino acids, both of which help activate mTOR and promote cell growth. The growth factors activate mTOR mainly via the PI-3-kinase–Akt pathway. Akt activates mTOR in complex 1 indirectly by phosphorylating, and thereby inhibiting, a GAP called Tsc2. Tsc2 acts on a monomeric Ras-related GTPase called Rheb . Rheb in its active form (Rheb-GTP) activates mTOR in complex 1. The net result is that Akt activates mTOR and thereby promotes cell growth
2.mTOR complex 2 -Contains the protein rictor and is insensitive to rapamycin; it helps to activate Akt , and it regulates the actin cytoskeleton via Rho family GTPases.
The Akt is phosphorylated on a serine by a third kinase (usually mTOR in complex 2), which alters the conformation of the Akt so that it can be phosphorylated on a threonine by PDK1, which activates the Akt. The activated Akt now dissociates from the plasma membrane and phosphorylates various target proteins, including the Bad protein. When unphosphorylated, Bad holds one or more apoptosis-inhibitory proteins (of the Bcl2 family—) in an inactive state. Once phosphorylated, Bad releases the inhibitory proteins, which now can block apoptosis and thereby promote cell survival.
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Members of the insulinlike growth factor (IGF) family of signal proteins, for example, RTKs stimulate many types of animal cells to survive and grow.
1.They bind to specific RTKs which activate PI 3-kinase to produce PI(3,4,5)P3.
2.The PI(3,4,5)P3 recruits two protein kinases to the plasma membrane via their PH domains—
a. Akt (also called protein kinase B, or PKB)
b. Phosphoinositide-dependent protein kinase 1 (PDK1), and this leads to the activation of Akt ).
3. Once activated, Akt phosphorylates various target proteins at the plasma membrane, as well as in the cytosol and nucleus.
4.Actions of Akt all conspire to enhance cell survival and growth.
The control of cell growth by the PI-3-kinase–Akt pathway depends in part on a large protein kinase called TOR (named as the target of rapamycin, a bacterial toxin that inactivates the kinase and is used clinically as both an immunosuppressant and anticancer drug).
TOR was originally identified in yeasts in genetic screens for rapamycin resistance; in mammalian cells, it is called mTOR, which exists in cells in two functionally distinct multiprotein complexes.
1. mTOR complex 1- Contains the protein raptor; this complex is sensitive to rapamycin, and it stimulates cell growth—both by promoting ribosome production and protein synthesis and by inhibiting protein degradation.
Complex 1 also promotes both cell growth and cell survival by stimulating nutrient uptake and metabolism. The mTOR in complex 1 integrates inputs from various sources, including extracellular signal proteins referred to as growth factors and nutrients such as amino acids, both of which help activate mTOR and promote cell growth. The growth factors activate mTOR mainly via the PI-3-kinase–Akt pathway. Akt activates mTOR in complex 1 indirectly by phosphorylating, and thereby inhibiting, a GAP called Tsc2. Tsc2 acts on a monomeric Ras-related GTPase called Rheb . Rheb in its active form (Rheb-GTP) activates mTOR in complex 1. The net result is that Akt activates mTOR and thereby promotes cell growth
2.mTOR complex 2 -Contains the protein rictor and is insensitive to rapamycin; it helps to activate Akt , and it regulates the actin cytoskeleton via Rho family GTPases.
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