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Signal transduction~4000 genes (16 % of genome) 25, 000 genes Signaling molecules 376(1. 2%) Receptors 1540 (5%) Kinases- 868 (2. 8%) Other components 968 (3. 2%) 320 cell types 700 Liver-specific genes

Chapter 15 - Cell Communication Part I- General signaling strategies Part II- G protein signaling Part III- Enzyme-linked cell surface receptors Part IV- Proteolysis-dependent signaling pathways

Outline Part I- General signaling strategies A. Two cell types B. A typical signaling pathway C. Most signaling molecules are hydrophilic (water loving) D. Some signaling molecules are hydrophobic (water hating) E. A review of membranes (from chapter 10) F. Signaling over short or long distances G. Autocrine signaling H. Cells respond to specific combinations of factors I. Signaling through gap junctions J. Different cells respond differently to the same signal molecules K. Nuclear receptors are ligand-activated gene regulatory protein L. Three classes of cell-surface receptors M. Common features of G protein-linked and enzymelinked receptors

Cell Communication Chapter 15 Part I- General signaling strategies A. Two cell types 1. Signaling cell Release Most secreted by • Proteins ______ or • ______ • Amino acids • _____________ • Dissolved gases (CO, NO) These are termed ____ 2. Target cell Respond by means of ______

BLA 512 1/5/98 update Cell surface receptor pathways Enzyme-linked Ion channel-linked G-protein-linked No details shown PDGF, EGF, IFa, b, and g, IL-2 , IL-3, IL-4, IL-6 TNFa TGF-b PLCg Gq Go PIP Adenylyl cyclase Ca++ from ER IP 3 PLCb Raf (a MAPKKK) c. AMP JNKK Smad NIK IKK STAT JNK Caspases Ik. B/NFk. B p 38 Elk-1 P TRADD FADD TRAF STAT MEKK MAPKKK Ik. B/NFk. B MAP-kinase (ERK) CREB MAPKKK (a MAPKKK) MAPKK (e. g. MEK) PKC PKA GNRPs (e. g. Sos) Ras DAG Smad Cell death jun JNK Gene Fos jun AP 1 STAT NFk. B Gene Nucleus P Elk-1 Fos Gene jun AP 1 Gene Cytoplasm Gs Golf AMP Grb 2 Jak G proteins Smad Gene

LPS-mediated apoptosis: Which pathway is defective? LPB LPS Fas. L TNFR Fas. R FADD Caspase 8 Sorb. CD 14 TRADD RIP TRAF 2 P 38 MAPK TPL-2 JNKK p 65 p 105 c-jun Calyculin A, Okadaic Acid PDTC NF-k. B P 105 phos, degraded IL 1 R 1 FADD Caspase 8 P 38 MAPK NIK MEKK 1, 2, 3 JNK TLR-4 TAK 1 TRAF 6 TGFBR My. D 88 IRAK TNF PKC EGFR IKK MEK ERK 1, 2 ALLN, HMA Apoptosis Ik. B SN 50 NF-k. B-responsive genes A 1, A 20, , Fas. L, TNF, Bcl 2, TRAF 1, 2, c-IAP 1, 2 Proteasome ROS PD 098059

Part I- General signaling strategies B. A typical signaling pathway

Part I- General signaling strategies C. Most signaling molecules are _____ (water loving) Thus, cannot cross plasma membrane D. Some signaling molecules are _______ (water hating) These may move easily through the plasma membrane

Part I- General signaling strategies E. A review of membranes (from chapter 10) 1. A typical membrane- a _________ with embedded _________

Part I- General signaling strategies E. A review of membranes (from chapter 10) 2. A membrane phospholipid ____ head ______ tail Composed of fatty acids

Part I- General signaling strategies 3. Membranes are composed of four major _______

Part I- General signaling strategies F. Signaling over short or long distances 1. _________ Requires _____ contact 2. ___________ a. Paracrine- act locally Fast-acting, _____, high concentration

2. Contact independent (continued) b. ______ Fast acting, ______ Part I- General signaling strategies c. _______ Slow, ________, low concentrations e. g. hormones

Part I- General signaling strategies G. _____ signaling Cell secretes signal molecules that bind back to own _______ Function- _____ decisions made by a group of cells.

Part I- General signaling strategies H. Signaling through ______ • Small molecules are shared through these ports • Ca++, c. AMP can pass, but not proteins or nucleic acids I. Cells respond to specific ______ of factors

Part I- General signaling strategies J. Different cells respond differently to the _______ signal molecules Example- acetylcholine

Part I- General signaling strategies K. Nuclear receptors are ________ gene regulatory proteins 1. Ligands include • __________- derived from cholesterol; produced in adrenal, ovary, testis • ________- increase cell metabolism • _______ - from vitamin A; impt. in development • _____ (UV synthesizes); Regulates Ca++ metabolism a. All are small, _____molecules carried by _____proteins b. Examples of signaling molecules that bind _____ receptors

Part I- General signaling strategies K. Nuclear receptors are ligand-activated gene regulatory proteins c. Nuclear Receptors- belong to _______ receptor superfamily d. All have three domains: 1. __________ domain Interacts with ______ 2. __________ domain 3. _________ domain

Part I- General signaling strategies K. Nuclear receptors are ligand-activated gene regulatory proteins e. Steroid hormones exhibit two response phases 1. _______ response genes activated

Part I- General signaling strategies K. Nuclear receptors are ligand-activated gene regulatory proteins e. Steroid hormones exhibit two response phases 2. ____ secondary response a. Primary response genes are _______ b. Secondary response genes _______

L. Three classes of cell-surface receptors Part I- General signaling strategies 1. _______-linked - (Transmitter gated ion channel) Example- _______ 2. _____-linked – Acts through a ____________(G protein) All are ______ transmembrane proteins

Part I- General signaling strategies L. Three classes of cell-surface receptors 3. ______-linked Includes _________ Most are ______ transmembrane proteins

M. Common features of G protein-linked and enzyme-linked receptor 1. Both become active via ________ 2. Both use phosphorylation _______ 3. Phosphorylation occurs at _______, _____or ____residues 4. ___% of mammalian genes encode these enzymes 5. Many are “_________”

M. Common features of G protein-linked and enzyme-linked receptor 6. These signaling complexes can either be on a ________. . .

M. Common features of G protein-linked and enzyme-linked receptor …. Or ________once the receptor is activated.

% max. activation 7. Cells can respond ______…. Conc. of effector molecules % max. activation M. Common features of G protein-linked and enzyme-linked receptors …. or _____ to increasing signal molecules

M. Common features of G protein-linked and enzyme-linked receptors 8. Cellular memory The response remains after the signal disappears How? 1. The ____ activates the receptor 2. Activate a __________ Example- Muscle cell determination. Turn on muscle-specific genes that regulate their own expression

Part I- General signaling strategies 9. Cells can also become _______ to the signal How? • Ligand binding cause ______ of receptor • Receptor _______ • _______ protein inactivated • _______ protein produced