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Transcript
Ligand Receptor Receptor/Ligand Binds to promoter elements in DNA and regulates transcription Cortisol Receptor is located in the cytosol Nucleus: Retinoid Receptors are in the nucleus Target gene in the nucleus Promoter Regulation of Transcription Primary and Secondary Responses Promoter Promoter Activation of transcription Inhibition of transcription K) There are three major classes of cell surface receptors extracellular space M) Signaling via G protein linked receptors adenylyl receptor G protein cyclase bg a membrane cytosol GDP ligand GTP ATP cAMP Pi cAMP Regulation of Transcription P CREB CRE Some G protein linked receptors linked to Gq activate Ca2+ signaling PIP2 plays an important role in Ca2+ signaling PI PIP2 Cleavage of PIP2 gives rise to Ca influx Gq PKC (PLC b) ER Ca2+ Calcium channel Calmodulin is a Ca2+ receptor that mediates many Calcium responses CAM Kinases mediate most Ca2+ responses CAM Kinase II Interactions between cAMP and Ca pathways cAMP phosphodiesterase and adenylyl cyclase are regulated by CAM Kinases PKA Ca channels Some CAM Kinases are PKA targets CAM Kinases and PKA common targets Regulation of Transcription Regulation of Phosphorylase Kinase by cAMP and Ca P CREB CRE e) phosphorylase kinase is regulated by cAMP and calcium 2) Receptor tyro sine kinase (RTK) family o f receptors Ligand binding usually causes dimerization of the receptor EGF EGF outside of the cell Membrane P P P P inside of the cell P-Tyr binds downstream regulators containing SH2 domains SH2 Domain PI3K P P GRB2 GAP P P PLC Ras pathway Ras superfamily of small GTPases help relay signals from RTKs Stimulus GEF GDP GTP Inactive Active GAP Downstream Signaling Pathways d) drosophila eye development and RTK signaling d) drosophila eye development and RTK signaling Mammalian Ras activation Drosophila Ras activation SH2 Domain PI3K P P GRB2 GAP P P PLC (DRK) SOS Ras GTP Downstream pathways MAP Kinase Pathways can be mediated by members of the Ras superfamily Stimulus Usually Ras superfamily Yeast MAP Kinase pat hways Mat ing/ Dif f erent iat ion . Cell Wall Int e grit y Osmot ic St re ss G bg Cdc4 2 STE 2 0 PKC1 STE 1 1 BCK1 SSK2 / 2 2 MAPKKK STE 7 MKK1 / MKK2 PBS2 MAPKK MPK1 HOG1 MA PK S T E 5 SSK1 KSS/ Fus3 Ca2+ signaling can be activated by RTKs via PLC g PI3K P P GRB2 GAP P P PLC Ca2+ signaling Cleavage of PIP2 gives rise to Ca influx RTK PLCg ER Ca2+ Calcium channel RTKs can activate PI3-Kinase Other signaling pathways Cell survival PI3K P P GRB2 GAP P P PLC PI3 Kinase (PI3K) PI(3)P CH2 C O O O CH OH- O CH2 O P CH2 C PhosphatidylInositol(PI) O PI3K CH2 C CH2 O 4 3 OH 6 2 OH- O 1 OH O CH2 O P 5 4 3 OH 6 2 1 OH CH2 C CH2 C O O CH O O 5 O CH2 O O O PI3K + PI4K PI(3,4,5)P2 PI(3,4)P2 OH- O CH2 C O O CH CH2 O P CH2 C CH2 O O OH- O 5 3 OH O 6 2 1 OH CH2 O P 4 5 6 3 OH 2 1 OH Cell Survival Pathways Other Signaling Pathways CH2 C O CH +PI5K O 4 O CH2 O O PI3 Kinase (PI3K) and cell survival pathways PI(3)P CH2 C O O O CH OH- O CH2 O P CH2 C PhosphatidylInositol(PI) O PI3K CH2 C CH2 O 4 3 OH 6 2 OH- O 1 OH O CH2 O P 5 4 3 OH 6 2 1 CH2 C CH2 C O O CH O O 5 O CH2 O O O PI3K + PI4K PI(3,4,5)P2 PI(3,4)P2 OH- O CH2 C O O CH CH2 O P CH2 C CH2 O O OH- O 5 OH 3 OH 4 1 OH PH AKT O 6 2 5 6 3 OH 2 1 OH PH P SER PDK1 ser BAD CH2 O P CH2 C O CH +PI5K O 4 O CH2 O O PI3K - AKT - Cell Survival AKT P SER BAD 1 4 -3 -3 P SER BAD BAD Mit ochondria BCL - 2 BCL- XL BCL - 2 BCL- XL cyt ochrome is released C Caspase Cacade Mit ochondria Inhibit ion of Cyt ochrome C r elease Cell Deat h Su r v iv al Tyrosine Kinase (TK) Associated Receptors LIGAND outside of the cell Membrane P P P P inside of the cell Src binds to receptors with and without Tyr Kinase activity Schwartzberg (1998) 17; 1463 PI3K P P GRB2 Src P P PLC Cell proliferation, Gene expression, … e) Janus family of non-receptor TK s also bind some receptors receptors i) growth hormone receptors ii) prola ctin receptors iii) some cytokine receptors LIGAND iv) include JAK1, JAK2, Tyk2 v) more poorly characterized P P Q) Signal Transduction and the Cytoskeleton