Signaling Pathways and Development Flashcards Preview

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Flashcards in Signaling Pathways and Development Deck (98):
1

What are two unique signaling pathways regulated by proteolysis?

-play crucial roles in embryonic development

Hedgehog pathway (Hh) and Wnt pathway

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Involved in maintaining stem cell niches in various tissues, including CNS, skin, and gut

Hh and Wnt

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The Hh and Wnt pathways have been implicated in

Cancer and tissue repair

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Diseases resulting from defects in Hh or Wnt can be either

1.) Congenital (inherited defects)
2.) Sporadic (Somatic mutations)

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What are the three members of the Hedgehog family?

1.) Indian
2.) Sonic
3.) Desert

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Necessary for the development of cartilage and bone

Indian Hh (Ihh)

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Necessary for the development of the central nervous system

Sonic Hh (Shh)

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Important in the development of peripheral nerves

Desert Hh (Dhh)

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What are the core components of the Hh pathway?

1.) Hedgehog
2.) Patched (Ptc) receptor
3.) Smoothened (Smo)
4.) Gli/Ci proteins
5.) PKA

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The hedgehogs are actually

Ligands

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Secreted hydrophobic proteins produced and secreted by localized groups of cells in both embryos and adults

Hedgehog (Shh, Ihh, and Dhh)

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12-span transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters

-binds Hh ligands

Patched (Ptc) receptor

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7-α-helix G-protein-coupled transmembrane protein

-Does not bind Hh

Smoothened (Smo)

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Does the patched receptor bind Hedgehog?

Yes

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Does the smoothened receptor bind Hedgehog?

No

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Transcription factors that can either activate or repress target gene expression depending on signaling status

Gli/Ci proteins

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Phosphorylates Gli/Ci proteins to target them for proteolysis in the proteosome

Protein Kinase A (PKA)

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Partially proteolyzed protein that acts as a transcription REPRESSOR

GliREP (Ci75)

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Full-length protein that functions as a transcriptional ACTIVATOR

GliACT (Ci155)

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Ptc not bound to Hedgehog acts as an

Inhibitor

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Ptc bound to Hedgehog acts as a

Receptor

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Sonic hedgehog transduction components localize to the

Primary Cilium

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Non-motile cilium that occurs singly on most cells in the vertebrate body

-critical sensors of extracellular information

Primary Cilium

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Numerous cilia proteins are involved in

Hh signaling

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Localize signal transduction components

Cilia

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Humans with ciliary defects can have problems with

Vision, Hearing, Smell, Left-right organ location (Situs Inversus), Kidney functions, and Hh signaling

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Congenital (inherited) human disorders of Hh signaling primarily affects the

Limb and CNS

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Localized to "organizing centers" in the limb buds and early CNS

Sonic Hedgehog (Shh)

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The ZPA morphogen

Sonic hedgehog

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Sonic Hedgehog controls digit pattern by graded inhibition of

Gli3 proteolysis

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Sonic hedgehog is required to inhibit the formation of

Gli3REP

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Defects in this ligand lead to decreased production of Dentate Gyrus Granule Cells (a CNS stem cell)

Sonic Hedgehog

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The product of over-proliferation of embryonic CNS progenitor ("stem") cells, indicating a link between Hh signaling and stem cell proliferation/maintenance

Exencephaly

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In the adult CNS, stimulating neurogenesis in resident stem cells may be of value in disorders including

Alzheimer's, Parkinson's disease, and Stroke

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The congenital diseases related to abnormal Hh signaling can be grouped by effect on

Hh pathway

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Can result from mutations in positive transduction pathway components

Diseases associated with reduced Hh signaling

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Diseases associated with reduced Hh signaling are associated with increased

Gli3REP activity

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An example of a disease associated with reduced Hh signaling is

Holoprosencephaly (HPE)

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A developmental disorder mainly characterized by incomplete midline formation during forebrain development

Holoprosencephaly (HPE)

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What is the incidence of holoprosencephaly?

4-8/100,000

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One of the most severe presentations of Holoprosencephaly (HPE) is

Cyclopia

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What are the traits shown in mice with Sonic Hedgehog knockout?

Cyclopia/holoprosencephaly and limb defects

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In HPE, pathogenesis is thought to result from

Shh protein haploinsufficiency

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When a single copy of a gene is not sufficient for normal function

Haploinsufficiency

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In cases resulting from Shh haploinsufficiency, the phenotype is limited to

-indicates that the developing structures likely have different sensitivities to reduced gene dosage

Brain/face defects (not other tissues)

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Have been found in both familial and sporadic cases of holoproencephaly

Mutations in Shh and Gli2

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HPE is caused by mutations that result in

Reduced Shh signaling

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Acts very similarly to mutations that result in reduced Hh signaling

Mutations that bock Smoothened (Smo) activation

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Inhibits Smo and results in HPE

Cyclopamine

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A 7-α-helix G-protein coupled transmembrane protein and a central component of the Hh signaling pathway

Smoothened (Smo)

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Not actually a receptor for Hh proteins

Smo

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Presents an attractive "druggable" target for manipulating Hh signaling in pathogenic conditions

Smo

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What are two natural compounds that antagonize Smo?

Cyclopamine and Jervine

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Mature Hh protein is generated from a longer precursor that undergoes a self-cleavage reaction that requires the addition of

Cholesterol

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The processed form of the protein containing a covalent cholesterol adduct is the

Active signalling species

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Mutations in the Shh gene in either the signaling domain or autocatalytic cleavage and cholesterol transferase domain will both cause

Holoproencephaly

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A prominent constituent of animal cells membranes, comprising up to 30% of the plasma membrane lipid content in some tissues

Cholesterol

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The first step of cholesterol synthesis requires

Acetyl CoA

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Which enzyme catalyzes the final step of cholesterol biosynthesis?

delta-7-reductase (DHCR7)

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Loss-of-function mutations for the sterol delta-7-reductase (DHCR7) gene are associated with

Smith-Lemli-Opitz Syndrome and HPE

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Encodes and enzyme that is critical in cholesterol synthesis

DHCR7 gene

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Cholesterol-reducing drugs in the group known as HMG-CoA reductase inhibitors should not be taken by women who are pregnant of who plan to become pregnant soon because they can cause

HPE

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What are two types of diseases that can result from increased or unregulated Hh signaling?

Congenital defects and cancer

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Can result from mutations in negative transduction pathway components

Increased or unregulated Hh signaling

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What is one potential way to treat increased or unregulated Hh signaling?

Cyclopamine or other Smo inhibitors

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Mutations that result in increased or unregulated Hh signaling lead to loss of

Gli3REP

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Mutations in GLI3 lead to loss of Gli3REP and are linked to which three related autosomal dominant syndromes that show limb and brain defects?

1.) Greig Cephalopolysyndactyly Syndrome (GCPS)
2.) Pallister-Hall Syndrome
3.) Postaxial Poydactyly Syndrome (PPS)

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Postaxial Polydactyly (PPS) results from

GLI3 haploinsufficiency

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A tumor arrising in the cerebellum during development

Medulloblastoma

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The most common malignant brain tumor in children

Medulloblastoma

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Medulloblastoma arises from granule neuron progenitors (GNPs) from the

Rhombic Lip

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In Medulloblastoma, there is a loss of function in

PTCH1

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Ptc1 +/- heterozygous mice have a 15-43% incidence of

Medulloblastoma

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Nevoid Basal Cell Carcinoma (skin cancer) patients (aka Gorlin Syndrome) that have mutations in PTCH1 have a 3-5% incidence of

Medulloblastoma

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Gene profiling of medulloblastoma shows an amplification of which Hh pathway proteins?

GLI1 and GLI2

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Medulloblastoma is an example of a disease which has shown

Drug resistence

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All tumor cells begin as a single abnormal cell. As the tumor cells grow in size, they accumulate additional mutations that increase

Malignancy

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Complicates tumor therapy

Genetic heterogeneity

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Can occur during tumor treatment

Clonal selection

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What are the two pathways for Wnt signaling?

Canonical and non-canonical

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The non-canonical pathway does not involve

β-catenin

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The Wnt ligand binds to the co-receptors

Frizzled/Frz and Arrow/Lrp

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When the Wnt ligand binds to the co-receptors Frizzled/Frz and Arrow/Lrp, the destruction complex is dissociated, interrupting

β-catenin phosphorylation

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Unphosphorylated β-catenin then enters the nucleus and binds

Tcf/Lef proteins

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Turns on gene expression

β-catenin binding to Tcf/Lef

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What do Tcf/Lef associate with in that absence of β-
catenin phosphorylation to block target gene expression?

Groucho/Grg co-factors

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Bi-functional transcription factors

Tcf/Lef proteins

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What are the two intracellular pools of β-catenin

1.) Cytoplasmic
2.) Cell membrane

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Involved in signaling and regulate gene expression

Cytoplasmic β-catenin

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Involved in cell adhesion/tissue homeostasis

-Associated with cadherins/adherins

Cell membrane β-catenin

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Phosphorylates β-catenin in the absence of Wnt signaling

"Destruction complex" (Axin, APC, and Gsk3)

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Phosphorylated β-catenin is degraded by

β-TrCP

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Further removes pgroups from β-catenin, leading
to itʼs stabilization

PP2A

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Can be altered by changes in β-catenin alone

Wnt Signaling

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Mutations in β-catenin that prevent phosphorylation promote stability and result in

Constitutive pathway action

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Strongly linked to colorectal cancer in FAP (famililal adenomatous polyposis)

APC (adenomatous polyposis coli) mutations

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Wnt and frat are both classified as

Proto-oncogenes

98

What are three tumor suppressors in Wnt signaling pathway?

Axin, APC, and Tcf1

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