Sorafenib Signal Transduction, VEGF Receptor Signaling in Angiogenesis

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, VEGF Production in Angiogenesis

VEGF Receptor Signaling in Angiogenesis, Activation of Ras

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Ras Activation of Raf/MEK/ERK

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Activating Mutations of Raf and Ras

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Ras/Raf/MEK/ERK Signaling

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Ras/PI3 Kinase Signaling

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Akt Signaling and Proliferation

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Ras/Raf/MEK/ERK Signaling

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Cyclin Dependent Kinase Regulation of Cell Cycle Genes

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, Akt Signaling and Cell Survival

VEGF Receptor Signaling in Angiogenesis, Sorafenib Signal Transduction, PI3 Kinase, Rac1 and Cell Migration

The VEGF family consists of:

• Glycoprotein homodimers that exhibit specific binding to VEGF receptors 1, 2 and/or 3

VEGF receptor 2 is considered to be the major mediator of VEGF-A angiogenic effects including:

• Cell proliferation
• Survival
• Migration

Soluble VEGF receptor 1

• Lacks transmembrane and intracellular regions
• Prevents VEGF-A binding to VEGF receptor 2

Hypoxia leads to:

• A sequence of molecular signals that results in the increased expression of VEGFA 
• Binds to VEGF2 receptors on vascular endothelial cells to promote angiogenesis

Expression of VEGF is regulated by HIF-1

• Hydroxylated by a family of oxygen-dependent prolyl hydroxylases
• Expression leads to increased production of VEGF which results in vascular endothelial cell survival
• Increases PDGF expression which leads to increased survival of other vascular cells

Phosphorylated tyrosine kinase receptor

• Interacts with the Src homology 2 domain or SH2 domain of the adapter proteins Shc and Grb2
• Grb2 through its SH3 domains recruits Sos to the plasma membrane
• Sos activates the small G protein Ras by promoting the release of GDP in exchange for GTP
• GTP bound Ras activates and interacts with a variety of effectors including Raf/MAP Kinase, PI3 Kinase and Ral-GEF

Ras

• Recruits Raf to the cell membrane

Activated Raf

• Phosphorylates MAPK Kinase or MEK which in turn phosphorylates ERK 1 and ERK2

ERK

• Phosphorylates and activates a variety of transcription factors

Sorafenib

• Blocks the activation of the serine/threonine kinase Raf in addition to multiple receptor tyrosine kinases

When activating mutations of Ras or Raf occur, these signaling molecules become capable of eliciting downstream mitogenic responses independent of receptor stimulation.

Sorafenib

• Blocks Ras and Raf signaling by directly inhibiting Raf kinase activity

• MAP Kinases or ERK 1 and 2 phosphorylate a variety of transcription factors
• ETS transcription factors have a highly conserved DNA binding domain
• Ternary complex factors binds to a low affinity ETS binding domain with serum response factor or SRF on a serum response element in the promoter regions of many immediate early genes
• The AP-1 transcription factors are made up of homo- and hetero-dimers of c-fos and c-jun
• ERK regulation of transcription effects the levels of gene products that control the cell cycle

Ras/Raf/MEK/ERK Signaling

Cyclin Dependent Kinase Regulation of the Cell Cycle

• Enzymes that lead the cell through the phases of the cell cycle

Cyclin Dependent Kinase Regulation of Cell Cycle Genes

• Regulate cell cycle progression is by phosphorylation of the tumor suppressor gene Rb

Tyrosine kinase growth factor receptors

• Activate PI3 kinase through Ras or independently of Ras
• PIP3 interacts with the pleckstrin homology domain of Akt to recruit Akt to the plasma membrane
• Akt is then activated through phosphorylation by PDK1 
• Activation results in tumor cell proliferation and survival

Akt

• Phosphorylates and inhibits a protein that allows for the activation of the mammalian target of rapamycin
• Contributes to cell cycle progression by decreasing the expression of cell cycle inhibitors

mTOR

• An evolutionarily conserved serine/threonine kinase that is inhibited by the drug rapamycin
• Phosphorylates the initiation factor 4EBP1
• Phosphorylates and activates p70 S6 kinase

4EBP1

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

Cyclin dependent kinases

• Enzymes that lead the cell through the phases of the cell cycle
• Phosphorylate crucial proteins involved in cell division
• Dependent upon another group of proteins, the cyclins
• Each interacts with a different set of cyclins

Cyclin dependent kinase inhibitors 

• Block the actions of the cyclin-CDK pairs
• INK4 CDK inhibitors block the effects of CDK 4 and 6
• p21Waf1/Cip1, p27Kip1 and p57Kip1 act more widely to inhibit all of the cyclin-CDK complexes that form later in the cell cycle

Cyclin dependent kinases

• Regulate cell cycle progression
• As cellular levels fall, cyclin-cyclin dependent kinase complex phosphorylates Rb

E2F transcription factor

• Mediates transcription of genes responsible for cell cycle progression

• Akt phosphorylates BAD 
• Bcl protein termed BAD binds to and inhibits the anti-apoptotic actions of Bcl-2 and Bcl-XL
• By inhibiting BAD, Akt promotes cell survival

Apoptotic cell death includes the loss of mitochondrial membrane integrity followed by the release of cytochrome C.

Rac1

• Small G protein 
• Can interact with downstream effectors PAK and LIM kinase
• A member of the Rho family of small G proteins

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