Cytoplasmic Signaling Circuitry Programs Many of the Traits of Cancer CHAPTER 6 Cytoplasmic Signaling Circuitry Programs Many of the Traits of Cancer Signaling cascades

A signaling pathway reaches from the cell surface into the nucleus Expression of immediate early genes

cycloheximide Immediate vs. delayed early genes

Serum-induced alterations of cell shape.

The Ras protein stands in the middle of a complex signaling cascade Structure of the fly eye. Son of sevenless

Tyrosine phosphorylation controls the location and thereby the actions of many cytoplasmic signaling proteins Domain structure of the Src protein

Structure and function of SH2 and SH3 domains

Attraction of signal-transducing proteins by phosphorylated receptors

Protein interaction domains as modular units of protein structure

Structure and function of Src

SH2 and SH3 groups explain how growth factor receptors activate Ras and acquire signaling specificity Intermolecular links forgets by the Grb2 and Shc bridging proteins

Ras-regulated signaling pathways: A cascade of kinases forms one of three important signaling pathways downstream of Ras The Ras effector loop

The Ras ->Raf ->MAP kinase pathway

Ras-regulated signaling pathways: a second downstream pathway controls inositol lipids and the Akt/PKB kinase The PI3K kinase pathway

Biochemistry of lipid bilayers

Activation of PI3K by Ras, growth factor receptors and somatic mutation.

Migration of PH-containing proteins to PIP3 in the plasma membrane

Docking of PH domains to PIP3

AKT/PKB and the control of cell growth

Ras-regulated signaling pathways: a third downstream pathway acts through Ral, a distant cousin of Ras Ral and the control of cytoskeleton

The Jak–STAT pathway allows signals to be transmitted from the plasma membrane directly to the nucleus

Constitutive activation of STAT3

Cell adhesion receptors emit signals that converge with those released by growth factor receptors Integrin signaling

Anoikis and morphogenesis

The Wnt–β-catenin pathway contributes to cell proliferation Multiple roles of b-catenin

Regulation of b-catenin signaling

G-protein–coupled receptors can also drive normal and neoplastic proliferation

Four additional “dual-address” signaling pathways contribute in various ways to normal and neoplastic proliferation

Deregulation of dual-address pathways in human cancers

Well-designed signaling circuits require both negative and positive feedback controls

Two-dimensional signaling maps

Ras effector pathways

Frequencies of oncogene activation in various human tumors

Structure of a signaling pathway

Homework: Due on 10/27 (Monday), 6 PM Handwritten only, no electronic version, within 5 A4 pages. Q: Please describe the Warburg effect of cancer cells. What’s the molecular mechanism and application?