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

Part III- Enzyme-linked cell surface receptors A. Properties: Transmembrane, ________, cytosol portion is ______ B. Six classes 1. Receptor _____________ - (cGMP production)- these use cGMP in same way as G-protein receptors use cAMP 2. Receptor _________________ Some common examples: _________growth factor (EGF) ___________ growth factor (PDGF) Fibroblast growth factor (FGF) _________ Insulin-like growth factor (IGF-1) _______ ______ growth factor (NGF) Notice that many are ____________

2. Receptor tyrosine kinases Part III- Enzyme-linked cell surface receptors Question- How can a signal be passed using a single ____________?? Answer- receptor ____________ followed by________________ on tyrosine residues Autophosphorylation a. Increases receptor enzyme _________ b. Creates ___________ for other __________ proteins.

How do these signaling proteins recognize the phosphorylated receptor? 2. Receptor tyrosine kinases Part III- Enzyme-linked cell surface receptors How do these signaling proteins recognize the phosphorylated receptor? Answer- By ____________- these recognize phospho-tyrosine Some have an _________ to interact with additional proteins

1. Ras proteins belong to a superfamily of _________ 2. Receptor tyrosine kinases Part III- Enzyme-linked cell surface receptors PATHWAY 3- Ras 1. Ras proteins belong to a superfamily of _________ 2. Stimulates cell ___________ or ______________ 3. ___% of human tumors have a hyperactive ras gene gene 4. _____ increase hydrolysis of bound GTP making ras ________ 5. _____ phosphorylate GDP to GTP, making ras _____

2. Receptor tyrosine kinases Part III- Enzyme-linked cell surface receptors PATHWAY 3- Ras The Ras GEF has no ___ domain, hence an intermediate protein called _____ is the adaptor protein for the ras GEF.

Ras activates a mitogen activated kinase (__________) pathway PATHWAY 3- Ras Part III- Enzyme-linked cell surface receptors Ras activates a mitogen activated kinase (__________) pathway Genes are activated Proteins are activated ___ _________ ________ ____ Each MAP kinase phosphorylates ___________ residues of next __________in cascade ____ _____

______________________________ Four families of MAPKs based on upstream activators and sequence similarities ______________________________ MAPKKK MAPKK MAPK Growth Inflammation/stress ___________ is common between pathways From: Tian et al. MAPK signaling and the kidney. A.m.J. Physiol. 279:F593-F604, 2000.

2. Receptor tyrosine kinases Part III- Enzyme-linked cell surface receptors The three-component MAP kinase pathways are sometimes “held together” by a ___________ Many MAP kinase components are shared by ___________ MAP kinase pathways Example- ________________ and _____________ sensing pathways use the same ____________ molecule Mating Molarity sensing

Phosphorylates phosphatidylinositol (PI) PATHWAY 4- PI 3-kinase Part III- Enzyme-linked cell surface receptors PI 3-kinase Phosphorylates phosphatidylinositol (PI) Note that this is ____ similar to G-protein transduction, because the ___ and _____ are NOT produced

Active PKB phosphorylates _____… PATHWAY 4- PI 3-kinase Part III- Enzyme-linked cell surface receptors PI 3-kinase stimulates cell growth and survival through _____________ (PKB) ( also called Akt) Active PKB phosphorylates _____… ….then ______ releases cell death inhibitor

Summary of the four pathways discussed 4 1 2 3

Problem: Some receptors cannot _______________other proteins 3. Tyrosine kinase-associated receptors Part III- Enzyme-linked cell surface receptors Problem: Some receptors cannot _______________other proteins Question: How do they signal?? Answer: By binding ________ proteins that can be phosphorylated (termed ________________________) These are mostly receptors for ______ (interleukins, interferons, tumor necrosis factor (TNF)) Example- Interferon signaling ___ and ____ bind the interferon receptor Jak and tyk2 __________ each other and the ______receptor

Pathway 5 - Jak/STAT pathway 3. Tyrosine kinase-associated receptors Part III- Enzyme-linked cell surface receptors Pathway 5 - Jak/STAT pathway Jak-STAT- an example of a ________________-___________ receptor pathway 1. __________ binds receptor 2. Jaks phosphorylate_____ _____ and receptor 3. ______bind phosphorylated receptor via ____ domain 4. STATs are phosphorylated 5. STATs __________, transport to _________ 6. STATs bind ___________, activate gene transcription

4. Protein Tyrosine phosphatase receptor (PTPs) Part III- Enzyme-linked cell surface receptors ~__ PTPs in human genome Cytoplasmic and __________ forms Responsible for most receptor ____________ in cells Remove phosphorylation from _________ residues

5. Receptor serine/threonine kinases Part III- Enzyme-linked cell surface receptors 5. Receptor serine/threonine kinases Function: Phosphorylate _____ and ________ residues on proteins Affect development, _________________, proliferation, ____________, immune regulation,…….. Includes ________________________ (TGF-b) superfamily TGF-b ______ superfamily Activins _____________ proteins (BMPs) PATHWAY 6- TGF-b

5. Receptor serine/threonine kinases Part III- Enzyme-linked cell surface receptors 5. Receptor serine/threonine kinases PATHWAY 6- TGF-b 1. TGF-b binds ___________. 2. _____ and ______ receptors interact 3. Type II receptor phosphorylates type I at ____________ 4. Phosphorylated type I _______ and ___________ Smad2/3

4. Smad2/3 interacts with ______ PATHWAY 6- TGF-b Part III- Enzyme-linked cell surface receptors 4. Smad2/3 interacts with ______ 5. Smad complex migrates to ________ 6. Smad complex binds TGF-b _____________ on DNA 7. Gene transcription is ________

Summary of tyrosine and serine/threonine kinases ________-specific protein kinases ___________-specific protein kinases