Sustaining Proliferative Signaling and Evading Growth Suppressors Oct 26, 2017

Hallmarks of Cancer, 2011

Epidermal Growth Factor Receptor -EGFR (aka ErbB1 or HER1) -tyrosine kinase receptor -3 other family members (HER2, HER3, HER4) -Binding partners include: -EGF -amphiregulin -neuregulins

EGF Signaling Pathway

Dimerization of EGFR -Conformation change upon binding, allowing domain II to interact -Can form heterodimers with other family members

Dimerization of EGFR -Phosphorylation of each of the Receptors by its partner

Signal Termination Multi-step process Additional phosphorylation, conformation change Inhibits EGF binding Dephosphorylation of tyrosine residues Binging of Negative regulators

Translocation of Proteins to EGFR -EGFR when phosphorylated attracts SH2 domain containing proteins -SH2 – Src homology 2 domain, -Binds to phosphorylated tyrosines -Grb2 – Contains SH2 domain and Binds EGFR-P -Contains a SH3 domain as well -SH3 – Src homology 3 domain -Binds to short proline-rich amino acid sequence -SOS – Son of Sevenless, contains the proline-rich sequence. -Activates RAS

Insulin Receptor Complex

Monomeric GTPases GAP – GTPase-activating protein GEF – Guanine nucleotide exchange factor

RAS Activation -RAS – GTP binding protein SOS GAP – GTPase-activating protein GEF – Guanine nucleotide exchange factor, SOS RAS- becomes farnesylated

Raf Activation -Activated RAS-GTP recruits Raf to the membrane -Raf is typically inhibited and RAS-GTP relieves the inhibition -Activated Raf can then phosphorylate MEK All kinases GTP

MAPK Activation -Activated MEK phosphorylates MAPK -Activated MAPK then enters the nucleus to phosphorylate transcription factors than can then alter their binding GTP

Transcription Factors -MAPK can activate AP-1 -Induces cell cycle progression by activating the Cyclin D gene -Composed of jun and fos proteins can act as a leucine zipper to Bind to DNA

Transcription Factors AP-1 activity in induced by 2 mechanisms: 1. jun becomes phosphorylated 2. MAPK activity increase sthrough other transcription factors the levels of jun and fos

MAPK induces Myc -MAPK targets several of the Myc family transcription Factors Myc family includes: Myc, Max, Mad, Mxi Myc and Max form a heterodimer of a helix-turn-helix leucine zipper Gene targets include: N-Ras and p53 and bind at the E box Max and Mad/Mxi heterodimer inhibit Myc and also bind at the E box but repress transcription

Mad/Mxi Myc Max Max

EGF Signaling Pathway

RAS Interacts with PI3K -Activated RAS brings PI3K to the membrane and converts PIP2 to PIP3 -PIP3 recruits PDK-1 to the membrane

Role of PIP3 -PIP3 recruits PDK-1 to the membrane -PDK-1 phosphorylates Akt

Akt Activities -Activated Akt is involved with anti-apoptotic and survival roles -mTOR, a kinase involved in promoting anabolic programming such as lipid and nucleotide syntheis

Akt Targets

EGF Signaling Pathway