BCOR 103 1st Edition Lecture 17 Outline of Last Lecture I. ReceptorsII. Receptor Tyrosine KinasesIII. Transmitters/Second Messengers Outline of Current LectureI. PKA ActivationII. Second MessengersIII. Kinases and Signaling ProteinsCurrent Lecture- PKA Activation also leads to Gene Inductiono cAMP binds to PKA regulatory subunits, leading to dissociation of catalytic subunitso Free catalytic subunits transport into nucleus to activate CRE binding proteinso CREB proteins bind cAMP Response Elements (CRE) and act as transcription factors to induce transcriptiono cAMP-induced genes control proliferation, cell survival, and differentiation- Phospholipids and Ca2+ as second messengerso Second messenger bonanza: PIP2 hydrolysis produces 2 second messengers: DAG and IP3 IP3 activates another second messenger: Ca2+*Where does PLC need to be targeted to hydrolyze PIP2?*How does it get there?- DAG Stimulates Kinase Cascades through PKCo Proteins Kinase C (PKC) Family of serine/threonine kinases Regulate cell growth and differentiation PKC function is regulated by DAG through open/closed model- IP3 Signals Release of Calcium StoresThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o Ca2+ affects activity of many target proteins including kinases and phosphatases- Ca2+ Signaling through Calmodulino Inactive calmodulin (has 4 Ca2+ binding sites)o Active Ca2+/calmodulin complexo Ca2+/calmodulin-dependent protein kinase (CaM kinase) o Interaction induces conformation change- Adenylyl Cyclase/cAMP Pathways have many Stimulio Signal-receiving capabilities of adenylyl cyclase isoforms and capability of PKA to regulate various physiological functions are shown- Small G Proteins: RAS GTPase as Molecular Switcho Guanine-nucleotide Exchange Factor (GEF)o GTPase Activating Protein (GAP)- MAP Kinase ERK Regulates Gene Expressiono Activated ElK1/SRF induces hundreds of genes, including transcription factors that furthers up-regulate gene expressiono Other induced genes encode small G proteins, enzymes, secreted molecules Serum Response Factor (SRF)- transcription factor Serum Response Element (SRE)- DNA sequence- Scaffold Proteins Nucleate Kinase Complexeso Scaffold proteins facilitate MAP Kinase interactions: Multiple kinases held together in complex by scaffold protein Components of kinase cascade may have dual role as scaffold and kinase- Regulation of Actin Cytoskeletono Actin cytoskeleton: regulates cell motility, shape, wound healing, etc. Rho family of small G proteins regulate cytoskeletal structure Cdc42, Rac, and Rho GTPases play similar roles in all eukaryotes- Rho GTPases Nucleate Multi-protein Complexeso Rho GTPases binding downstream effectors releases effectors from auto-inhibtiono Leads to activation of kinases (PAKs, ROCK) or to interactions with other proteins (WASP)- Drosophila Development and Differentiationo Developmental biology: gene activation and protein interactions during lifetime of morphological changes.o Morphological changes in drosophila (fruit fly) can be studied from egg through adulthood.o Proteins involved in drosophila development, with few exceptions, are same as those involved in development of higher organisms.o Drosophila is just one level of magnitude less complex than human.- Signaling during compound eye developmento Each unit of compound eye is composed of eight photoreceptor neurons (R1-R8) that develops in fixed order and patterno R8 differentiates first, then induces two neighboring cells to become R2 and R5o R2 induces neighboring cells to become R1 and R3, and R5 induces neighboring cells to become R4 and R6o Cell to cell interactions between R8 and undifferentiated neighbor cell leads to differentiation R7- R7 Differentiation is through Cell to Cell Signalingo Seven-less mutants: fly missing R7 in every photoreceptor unit of