Temsirolimus, Temsirolimus Signal Transduction, Growth Factor Receptor Activation

Temsirolimus, Temsirolimus Signal Transduction, Growth Factor Receptor Signaling in Tumorigenesis

Temsirolimus, Temsirolimus Signal Transduction, Activation of Ras

Temsirolimus, Temsirolimus Signal Transduction, Akt Signaling Activation of mTOR and Proliferation

Temsirolimus, Temsirolimus Signal Transduction, Akt Signaling and Cell Survival

Temsirolimus, Temsirolimus Signal Transduction, VEGF Production in Angiogenesis

Growth factor binding to tyrosine kinase receptors leads to receptor dimerization and transphosphorylation.

Tyrosine kinase growth factor receptors

• Activate PI3 kinase through Ras or independently of Ras

PI3 kinase

• Catalyzes the conversion of the lipid phosphatidyl inositol bisphosphate to phosphatidyl inositol trisphosphate

PIP3

• Interacts with the pleckstrin homology domain of Akt to recruit Akt to the plasma membrane

Akt

• Activated through phosphorylation by PDK1
• Signals cascades resulting in tumor cell proliferation and survival

Phosphorylated tyrosine kinase receptor

• Able to interact with the Src homology 2 domain or SH2 domain of the adapter proteins Shc and Grb2

• Grb2 recruits Sos to the plasma membrane
• Sos activates the small G protein Ras 
• GTP bound Ras is activated and interacts with a variety of effectors

Akt

• Phosphorylates and inhibits protein TSC

mTOR

• Serine/threonine kinase inhibited by the drug rapamycin
• Phosphorylates the initiation factor 4EBP1 
• Phosphorylates and activates p70 S6 kinase also known as S6 kinase
• Activation regulated by cell stress, amino acid, and ATP availability and hypoxia

4EBP1

• Binds to and inhibits eLF4E
• Phosphorylation releases eLF4E allowing for initiation of translation

BAD

• Phosphorylated by Akt inhibiting pro-apoptotic ability
• Binds to and inhibits the anti-apoptotic actions of Bcl-2 and Bcl-XL
• These proteins prevent the release of cytochrome C release from the mitochondria
• Inhibition promotes cell survival

One of the early events in apoptotic cell death includes the loss of mitochondrial membrane integrity followed by the release of cytochrome C.

HIF-1

• Regulates expression of VEGF
• Hydroxylated by a family of oxygen-dependent prolyl hydroxylases under conditions of normoxia
• Ubiquitination targets it for degradation
• When levels are low cannot act as a transcription factor for VEGF production

As tumor cells grow:

• Supply of oxygen cannot keep up and becomes hypoxic
• HIF-1 levels accumulate, and HIF-1 enters the nucleus
• HIF-1-mediated expression of VEGF occurs, leading to the accumulation and release of VEGF
• Increased vascular supply leads to additional tumor growth

Recent studies have shown that signaling through the PI3 kinase-mTOR pathway inhibits the accumulation of HIF-1 and hypoxia-induced HIF-1-dependent gene transcription.

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