BCOR 103 1st Edition Lecture 17 Outline of Last Lecture I Receptors II Receptor Tyrosine Kinases III Transmitters Second Messengers Outline of Current Lecture I PKA Activation II Second Messengers III Kinases and Signaling Proteins Current Lecture PKA Activation also leads to Gene Induction o cAMP binds to PKA regulatory subunits leading to dissociation of catalytic subunits o Free catalytic subunits transport into nucleus to activate CRE binding proteins o CREB proteins bind cAMP Response Elements CRE and act as transcription factors to induce transcription o cAMP induced genes control proliferation cell survival and differentiation Phospholipids and Ca2 as second messengers o 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 PKC o 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 Stores These 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 Calmodulin o Inactive calmodulin has 4 Ca2 binding sites o Active Ca2 calmodulin complex o Ca2 calmodulin dependent protein kinase CaM kinase o Interaction induces conformation change Adenylyl Cyclase cAMP Pathways have many Stimuli o 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 Switch o Guanine nucleotide Exchange Factor GEF o GTPase Activating Protein GAP MAP Kinase ERK Regulates Gene Expression o Activated ElK1 SRF induces hundreds of genes including transcription factors that furthers up regulate gene expression o 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 Complexes o 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 Cytoskeleton o 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 Complexes o Rho GTPases binding downstream effectors releases effectors from autoinhibtion o Leads to activation of kinases PAKs ROCK or to interactions with other proteins WASP Drosophila Development and Differentiation o 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 development o Each unit of compound eye is composed of eight photoreceptor neurons R1 R8 that develops in fixed order and pattern o R8 differentiates first then induces two neighboring cells to become R2 and R5 o R2 induces neighboring cells to become R1 and R3 and R5 induces neighboring cells to become R4 and R6 o Cell to cell interactions between R8 and undifferentiated neighbor cell leads to differentiation R7 R7 Differentiation is through Cell to Cell Signaling o Seven less mutants fly missing R7 in every photoreceptor unit of eye