Exam 4: Lecture 4 Flashcards Preview

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Signal Tranduction Cascade

-typically will involve the production of ligand by sending cell
-this molecule will bind to cell surface transmembrane receptor on receiving cell
-activation of receptor will lead to transmission of instructions to nucleus through serial activation of several cytoplasmic factors
-most downstream member of cascade translocates into nucleus where it will physically modify transcription factors (usually via phosphorylation)


Phosphate Groups

-addition to TFs can sometimes lead to inactivation of protein
-or can lead to activation



-proteins secreted at one cell to act at a distance to influence the cells that it surrounds.


Paracrine Signaling

-used by long range signaling gradient
-diffuse past most immediate cell neighbors and will make contact with receptors located further away from sending cell
-some signaling molecules are first generated as larger proteins that can be tethered to surface of sending cell plasma membrane
-in response to cleavage event, biologically active ligand can diffuse away-also signal at both short and long range distances


Morphogen Gradient

-ligand which is produced and secreted from small population of cells is capable of travelling several cell diameters
-Each receiving cell will express the same number of receptor molecules
-however cell closest to sending cell will have highest number of occupied receptors
-more distant cells have fewer occupied receptors
-gradation in receptor-ligand binding can lead to differential levels of activated transcription factors which influences gene expression


Gradient Levels and Transcription

-cells that are closest have highest levels of ligand-receptor bound complexes.
-leads to highest level of activated TF and in turn all 3 target genes (A, B, and C) actively transcribed
-intermediate cells have fewer occupied receptors and therefore less activated TFs and only genes B and C transcribed
-far cells have least number of occupied receptors and activated TFs so only gene C is transcribed.
-picture on slide



-secreted by ventral follicle cells that surround developing Drosophila embryo.
-capture of this ligand by Toll receptor leads to translocation of Dorsal TF into nucleus
-vast majority captured by receptors on ventral cells
-remaining captured by Toll receptors on lateral cells
-dorsal receptors never receive


Juxtacrine Signaling

-tethered to membrane and are never cleaved or secreted by sending cell
-can only signal to cells directly contacting sending cell
-some cases ligand-receptor complex will be internalized within receiving cell
-other cases simple binding of tethered ligand to transmembrane receptor is sufficient to activate receptor and initiate signal transduction


Autocrine Signaling

-situations in which diffusible ligand is secreted by ell then binds to cell surface receptors on same side of cell
-leads to biochemical changes within same cells
-cells that respond to its environment and releases proteins into cellular membrane, but only affects itself


Intracrine Signaling

-ligand or hormone enters cell and goes straight to nucleus without interacting with receptors at cell surface
-once in nucleus, bind to nuclear receptors
-together steroid-receptor complex will bind to DNA and activate/repress transcription of target genes



-ligand/morphogen is secreted into circulatory system to be carried to distant organ or cell population


Determining Ligand Diffusion Distance

-see example on slide


Mechanism of Receptor Tyrosine Kinase Activity (RTK)

-mediates many signal transduction cascades
-prior to signal activation, ligand and receptors not bound to each other
-absence of ligand, receptors exist as monomers within plasma membrane
-binding of ligands and receptors changes conformation of receptor so they can physically interact with each other within plasma membrane
-RTKs form dimer complexes
-dimerization triggers activation of kinase domains located in cytoplasmic sections of receptors
-kinase domain is responsible for adding phosphate groups
-RTKs trans phosphorylate each other at conserved tyrosine amino acids located within cytoplasmic sections of protein
-phosphorylated receptor now active and will stimulate activity of cytoplasmic proteins


Mechanism of Receptor Tyrosine Kinase Activity (Cytoplasmic Signaling Cascade)

-binding of ligand to RTK leads to dimerization and transphosphorylation of receptor
-leads to activation of cytoplasmic signaling cascade
-first molecule activated is Ras which is a GTPase
-Ras activates cytoplasmic Raf kinase
-Raf kinase phosphorylates and activates MEK
-MEK phosphorylates and activates MAPK
-unphosphorylated MAPK found in cytoplasm and dually phosphorylated version is translocated into nucleus
-after MAPK enters nucleus it will phosphorylate several TFs
-some activators will then promote gene expression
-other receptors inhibit gene expression.



-all RTKs transmit signals to nucleus through Ras/MAPK signaling cascade
-activation of different RTKs will lead to modification of very different transcription factors
-different RTKs can function in different tissues while multiple RTKs can also function within same cell


Toll Receptor

-unbound toll receptors bound by Tube and Pelle proteins
-when Spatzle ligand binds to Toll receptor the two proteins are released from receptor and quickly bind to Cactus
-before Toll receptor activation, Cactus binds and sequesters Dorsal TF in cytoplasm
-when Tube and Pelle released from Toll receptor they bind and participate in degradation of Cactus
-allows Dorsal protein to enter nucleus and activate transcription of target genes (twist, rhomboid, and sog)


Notch Pathway

-Delta ligand binds to Notch receptor and Notch receptor is then bound by cytoplasmic scissor protein Kuz
-Kuz cleaves intracellular domain of receptor Nicd
-Nicd then translocated to nucleus where it interacts with Su(H) DNA BP
-absence of Notch signaling Su(H) physically interacts with C terminal BP (CtBP) and Groucho (Gro) co-repressors to inhibit transcription
-Nicd displaces both of these which turns Su(H) into transcriptional activator
-cells that express Notch receptor become non-neuronal cells while those that express Delta become neurons


Hedgehog Pathway

-absence of Hh ligand and Patched (Ptc) receptor will bind to and inhibit activity of another membrane receptor called Smoothened (Smo)
-within cytoplasm dozen proteins bound together as complex whose role is to partial degrade Tf called Cubitus Interruptus (Ci)
-smaller factor enters nucleus and functions as transcriptional repressor
-Hh ligand binds to Ptc receptor preventing it from binding to Smo receptor
-consequently they cytoplasmic protein complex dissociates and full-length Ci protein is allowed to enter nucleus.
-full-length Ci is activator