Download Biology 340 Molecular Biology

Biology 340 Molecular Biology
Lectures 27 & 28
Cell Signaling
April 25 & 30, 2001
Reading: Chap. 20, Lodish et al. pp. 848-858, 871-878, Fig. 20-48b
Outline:
1. Overview
a. signaling molecules
c. cell surface receptors
d. downstream signaling proteins
2. Receptor tyrosine kinases & ras
a. ligands
b. receptors
c. ras and adaptor proteins
d. nuclear signaling via SRF
Lecture
1. Overview of extracellular signaling

Signal transduction: process of converting extracellular signals into
cellular responses.

Signaling molecules: small molecules, peptides, proteins

Receptors: cell surface proteins specific to particular signaling molecules
STEPS:
1.
2.
3.
4.
5.
6.
Synthesis of extracellular signaling molecule
Release of signaling molecule from cell
Transport of signal to target cell
Signal binds to receptor on target cell
Binding triggers cellular change
Removal of the signal
Three types of signaling molecules
 Endocrine: secretion of hormone in blood--acts on distant target cells
 Paracrine: adjacent target cell
 Autocrine: target sites on same cell
Ligand: Cell signaling molecule that binds a particular receptor.
1
Receptor protein:
 Shows binding specificity for particular ligand
 Receptor-ligand complex mediates a specific cellular response=effector
specificity.
Types of hormones
1. Small lipophilic molecules that diffuse across plasma membrane and interact
with intercellular receptors. Complex of ligand and receptor moves to nucleus to
activate transcription.
Examples: Steroids, thyroid hormone, retinoic acid, vitamin D
2. Hydrophilic molecules that bind cell surface receptors.
Examples: peptide hormones (insulin, glucagons), small charged molecules
(epinephrine)
3. Lipophilic hormones with cell surface receptors
Prostaglandins--16 different molecules
Types of cell-surface receptors that interact with hydrophilic ligands
1. G-protein coupled receptors
 receptors for epinephrine, serotonin, glucagon
2. ion channel receptors
 acetylcholine receptor at neuromuscular junction
3. tyrosine kinase linked receptors
 receptors for cytokines, interferons, HGF
4. receptors with intrinsic enzyme activity
 receptors for insulin, many growth factors
Second messengers: intracellular signaling molecules that transmit signal from
ligand-receptor complex to other molecules in the cell.
Intracellular signaling proteins
1. GTPase switch proteins
 act as molecular switches
 on when bound to GTP
 off when bound to GDP
2

two classes: ras family (monomeric), trimeric G-proteins
2. Protein kinases
 enzymes that add a phosphate group to other proteins
 major types: serine/threonine kinases, tyrosine kinases
 activity of kinases opposed by protein phosphatases
3. Adapter proteins
 link cell signaling proteins via protein-protein interactions
Receptor tyrosine kinases





NGF, nerve growth factor
PDGF, platelet derived growth factor
FGF, fibroblast growth factor
EGF, epidermal growth factor
Insulin
1. Ligand binds receptor
2. Activates receptor's intrinsic protein kinase activity.
 Most RTKs dimerize on binding ligand (insulin already a dimer) and
phosphorylate tyrosines on dimer partner.
 Phosphotyrosines may serve as docking sites for other downstream
signaling proteins.
3. Stimulate signal transduction cascade.
 Ras (a GTP switch protein) is a key signaling molecule.
 Mutant ras has been associated with many human cancers.
 Ras is linked to RTK via adaptor proteins such as GRB2 and Sos.
4. Changes in cellular physiology and/or patterns of gene expression.
 Ras induces a kinase cascade that lead to activation of MAP kinase and
ultimately to phosphorylation of transcription factors.
 Kinase cascades allow a huge amplification of the initial signal.
 TCF (ternary complex factor) is a transcription factor phosphorylated by
MAP kinase that along with SRF (serum response factor) activates genes
contain SREs (serum response elements), Fig. 20-48b.
3