Chapter 5 Lecture Flashcards

Epithelial Cells

line internal and external surfaces of the body

Endothelial Cells

specialized epithelial cells, line internal surfaces of components of the circulatory system

Growth Factors (GFs)

proteins that act as mitogens

Mitogens

induce cell division/enhance division rate

GF Intercellular Communication

small molecules communicate between neighboring cells

PDGF

potent stimulator of fibroblasts, found on mesenchymal cells (e.g. fibroblasts, adipocytes, smooth muscle cells, glial cells)

Tyrosine Kinase

adds phosphate group to another protein from ATP

EGF Receptor

tyrosine kinase, binds to own receptor, first GF discovered, found on epithelial cells

ErbB Oncogene

resembled truncated EGF receptor, involved in breast cancer

What are some of the types of receptors used for cell signaling?

GF receptors, cytokine receptors, TGF-Beta receptors, notch receptors, patched-smoothened

Growth Factor Receptors

bind to tyrosine kinase receptors (RTK), act as ETK when active, are homodimeric

Homodimeric

has two subunits

Transphosphorylate

adding a phosphate group to tyrosine tails

Cytokine (Interferon) Receptors

in immune cells, use cytokines

Cytokine

chemical messengers

roles in cell signaling, directing immune cells to sites of infection/injury, cell activation, migration, tissue repair, differentiation

EPO

erythropoietin, hormone produced by the kidneys to stimulate RBC production

TPO

thrombopoietin, hormone produced (primarily) by liver and kidneys to regulate platelet production

Interleukin, Interferon

produced by leukocytes, involved in immune response

Type-II TGF-Beta

takes phosphate from ATP and adds it to serine/threonine kinase, recruiting the other dimer and activating the cytoplasmic tail

Type-I TGF-Beta

starts the signal cascade in the cytoplasmic region of the cell

Notch Receptor (Juxtacrine Signaling)

commonly mutated in thyroid cancers and T cell leukemia, has 36 EGF-like domains in the extracellular region

Patched-Smoothed

both names are receptors used in the signal cascade that results, work together to regulate transcription and gene expression

Where is the RAS protein linked?

to the inner surface of the cell membrane

What is the overall goal of cancer treatment?

to find the most effective treatment with the least amount of side effects, meaning targeted treatment is preferred

How do oncogenes trick cells?

by acting as though GF is present

Give an example of how oncogenes trick cells

they change the protein structure of the receptor, can change it in various ways

When do normal cells divide?

only when signals to do so are received by neighboring cells

If there is no PDGF, what happens?

fibroblasts don’t divide, but remain viable and metabolically active for weeks in a Petri dish

Describe an experiment that was done to look at how PDGF affects cell growth

two dishes of fibroblasts were grown, the surface of one was scratched with PDGF, the plate with PDGF grew colonies covering the entire bottom of the plate, the plate with no PDGF grew nothing

Describe an experiment using fluorescent tagging to look at the effect growth factors have on cancer cells

growth factor EGF was tagged with fluorescent proteins and mouse carcinoma cells were stained with red fluorescence, the cancer cells moved toward the EGF, showing presence of GF enhances cell motility and cell division

What was the first studied oncogene? Describe it

Src, it is a tyrosine kinase

Why are signal cascades useful?

they allow better control and protection for the cell, helps the cell manage what is going on, “fine tuned control”

How does v-src relate to EGF?

there are regions of homology between these two proteins and the v-src behaves like an active EGF

What happens if the ectodomain of ErbB is cut?

it is always found in its active state

What do receptor mechanisms help explain regarding cancer cells’ constant divisions?

explains why cells keep getting the signals to divide

Describe how normal cells receive signals to divide

ligand GF binds to receptor → activates the cytoplasmic talk

Describe how cancer cells receive signals to divide

cytoplasmic tail has a mutated code or is truncated to be always active, can also be overexpressed by having too many receptors on cell surface

Describe normal paracrine signaling

GF made in one cell type and binds to a receptor on another cell type (e.g. epithelial makes, mesenchyme receives), has regulation and control

Describe what happens to paracrine signaling (what it changes to) in cancer cells

paracrine turns into autocrine signaling where the cancer cell produces its own GF, removing control and regulation from the process

Describe the steps taken during GF receptor tyrosine kinase receptor signaling

1. external subunits come together allowing the GF to bind

2. GF binds, causing the subunits to transphosphorylate each other, activating the cytoplasmic tail

What are some other possibilities the subunits could take during RTK signaling?

GF binds to one of the subunits, causing the other to come towards the first subunit

What are RTK oncogenes a result of and what can they cause?

result of gene fusion events, can cause dimerization or constitutive receptor activation in some tumors

Describe the process of cytokine reception and binding

cytokine binds to proper receptor, causes receptor tails to transphosphorylate, receptor now active and starts signal cascade

What can control the development of abnormal hematopoetic cell types?

Jak protein

Why is the TGF-beta receptor unique?

it is able to either decrease cell division function or promote the invasion of transformed (cancer) cells

Describe the process of notch receptor signaling

ligand binds → some of the extracellular portion of the receptor is cleaved by protease → product of the cleaving reaction is sent down the tail of the protein to the nucleus → transcription factors blockers are inhibited and transcription is initiated influencing gene expression → cleaved receptor part taken for endocytosis from cell

What is required for cells to be able to use notch receptor signaling?

cells must be in close proximity so the notch can bind to delta ligand

What is the mutant form of the notch receptor able to do/is like?

mutant is always active and fires independently from ligand

Describe what is occurring if the patched-smoothened receptor is not making the ligand

the smoothed receptor is blocked since Hedgehog is absent

What happens in the patched-smoothened receptor path when the Hedgehog protein is present?

Hedgehog binds patched → conformational change → smoothened travels to gli → gli protein taken to the nucleus → gene expression of proteins needed for cell division induced

Canonical Wnt Signaling

B-catenin involved, ligand = Wnt, co-receptor protein = LRP, receptor = Frizzled

involved in cell proliferation and regulating gene expression

How was Wnt signaling discovered

by observing Drosophila wingless mutants

How many Wnt species are in humans?

19

Where are the receptor proteins in Wnt signaling located

tethered to the ECM, so ligands not freely diffusible

B-catenin

proliferation promoting protein, phosphorylated in the Wnt signaling pathway

What happens to B-catenin when Wnt binds?

it degrades meaning there will be no cell division

Describe the general process of the canonical Wnt signaling pathway

Wnt binds to Frizzled, GSK kinase inactivates, no phosphorylation occurs, increased amount of B-catenin

Apc

protein mutated in many cancers, including FAP colon cancer where many polyps develop

Non-canonical Wnt Signaling

ligand = Wnt, receptor = Frizzled, uses G-protein system with alpha, beta, and gamma subunits

roles in cell division, cell motility, self-renewal, invasiveness

When is Non-canonical Wnt Signaling inactive?

when Wnt not bound to receptor and GDP bound to G-protein

When is Non-canonical Wnt Signaling active?

when Wnt is bound to receptor and G-protein is bound to GTP

Describe the general process of the Non-canonical Wnt Signaling pathway

Wnt binds to Frizzled, alpha and beta subunits activate, exchange of GDP to GTP, alpha subunit separates, which activates enzymes that promote cell division, beta subunit activates PLB which activates PKC

PKC (Protein Kinase C)

protein important for increasing cell division and regulating glucose uptake

How does the Non-canonical Wnt Signaling pathway turn off?

alpha subunit hydrolyzes GTP to GDP, re-associating beta and gamma

SERM

selective estrogen receptor modulator, ligand estrogen mimicker

Nuclear Receptors

receptors on the nuclear membrane (hydrophobic with small MWs), can transverse the membrane and bind to nuclear TFs

Where do ligands bind regarding nuclear receptors?

in the cytoplasm or on chromatin

What other protein structure is near gene promotors?

hormone response elements

Epigenetics

the study of how behaviors and environment change gene expression

Methylation

winds DNA tighter, reducing gene expression, adds methyl groups

Acetylation

winds DNA looser, increasing gene expression, adds acetyl groups

associated with oncogenes

Tamoxifen

type of estrogen mimicker used for breast cancer treatment after eradication, prevents re-occurrence

Describe generally how Tamoxifen works

binds the estrogen receptor, blocks estrogen signaling OR recruits repressor proteins that prevent transcription and division of cells

Integrins

interact with the ECM

roles in structural support, cell communication, regulate various cellular processes

ECM

extracellular matrix, cells produce proteins: collagen, lamini, fibronectin, proteoglycans

Describe the interaction between cancer cells and the ECM

cancer cells must move around so they break ECM attachments to increase their motility

Integrin Structure

alpha and beta subunits, cytoplasmic tails interact with other molecules

RGD receptors

recognize Arginine-Glycine-Aspartate tripeptide (Arg-Gly-Asp) in integrin

What regulates attachment, adhesion, and motility of cells regarding integrins?

the tethering complex between proteins inside and outside of the cell

Ras Oncogene

mimics GFs and integrins, functions as a G protein (GTPase if active), can hydrolyze own GTP to GDP using GAP

What brings Ras activity back to its inactive state?

GTPase protein activity

GAP

GTPase activating protein

GEF

guanine exchange factor, removed GDP and adds GTP to Ras turning on downstream signaling

What makes Ras unique regarding signaling?

can trigger up and downstream mechanisms

What kinds of mutations can make a Ras oncogene?

point mutations in Ras, GEF, or GAP

Upstream

initiation of a signal

Downstream

responsible for the final outcomes of a reaction, the steps that lead to a cellular response