What does ligand binding promote in RTK signaling?
dimerization and phosphorylation of tyrosine amino acid
What activates receptor tyrosine kinases?
the binding of the ligand
Which part of an RTK signal is variable and which is conserved?
Extracellular N-terminal is variable and intracellular C-terminal is conserved
What are examples of families of RTK receptors?
EGFR, InR, VeGF, FGFR
What do RTKs directly activate?
What does cross-linking do?
activates tyrosine kinase activity by phosphorylation
what is cross-phosphoyrlation?
each RTK in the dimer phosphoyrlates multiple tyrosines on the other RTK
What happens to RTKs after they are phosphorylated?
they serve as docking platforms for intracellular proteins.
What is Grb2?
an adaptor protein with SH2 and SH3 binding domains required for EGFR signal transduction.
What does RTK signaling ultimately do?
leads to changes in gene expression
What makes signaling complex?
crosstalk between intermediates in various signaling pathways in the cell as the signal travels from the membrane to the nucleus.
How do RTKs activate Ras?
by causing it to bind to GTP
what is Ras?
a protein that is tethered to the plasma membrane
What does Ras do once activated?
activates an enzymatic cascade of MAP kinases resulting in potential changes in the cell such as alteration in key proteins and changes in gene transcription
What are growth factors?
signaling molecules that bind to RTKs.
What do growth factors do?
direct cell differentiation and proliferation by determining patterns of gene transcription.
Other than lingands, how can RTKs be activated?
by ECM proteins and surface proteins such as ephrins.
What are ErbB2 and HER2 overexpression linked to?
breast cancer recurrence and poor prognosis. It is also the target of Herceptin
What are three ways hyperproliferation can be fixed?
1. neutralizing antibodies block the bioactivity of RTK ligands.
2. TRK targeted antibodies either target overexpressed receptors or receptor heterodimerization
3. small-molecule inhibitors of RTK kinase interfere with RKS signal transduction.
What is Ephrin?
membrane bound ligands that signal through Ephrin receptors
How does Ephrin signaling occur?
forward and reverse.
What is Ephrin signaling involved in?
developmental processes, including axonal guidance and cell migration.
What role does Ephrin signaling play in adults?
angiogenesis and stem cell differentiation.
How does Ephrin sginaling work in developmental processes?
mediating a repulsive signal
How do RTKs differ from other cell surface receptors?
They contain intrinsic enzyme activity
What is cell adhesion signaling?
To preserve proper tissue architecture, adhesive molecules help maintain contact between nearby cells and structures, an dtiny tunnel-like junctions allow the passage of ions and small molecules between adjacent cells.
What do cell adhesion signaling molecules relay?
positional information among the cells in a tissue as well as the cells and the extracellular matrix.
Why are cell adhesion signaling pathways important?
they are critical in maintaining the state of equilibrium known as homeostasis within a tissue
What are integrins?
adhesion molecules that allow cells to maintain contact with the ECM and connect it to the actin cytoskeleton.
What is the function of an integrin?
keep the cell adhered to the ECM and send intracellular signals controlling cell shape and migration as it senses the extra cellular environment.
What are integrins made up of?
two subunits (alpha and beta)
What do integrins form?
How do integrins connect to the inside of the cell?
binds to adaptor proteins that connect to the actin filaments inside the cell
Why are integrins important in a migrating cell?
endocytosis and recycling of integrin heterodimers at the leading edge are important for the correct turnover and assembly of adhesion sites.
What happens to internalised integrins?
they are ubiquinated and sorted to lysosomes via multivesicular endosomes.
What are tight junctions?
between cells are connected areas of hte plasma membrane that stitch cells together.
What are adherens junctions?
join the actin filaments of neighboring cells togther.
What are desmosomes?
stronger connections that join the intermediate filaments of neighboring cells.
What are hemidesmosomes?
connect intermediate filaments of a cell to the basal lamina, a combination of extracellular molecules on other cell surfaces.
What are gap junctions?
cluster of channels that form tunnels of aqueous connectivity between cells.
How are cells linked togheter?
side-to-side junctions of proteins with diverse makeup and function interact with similar proteins on adjacent cells.
Where do transmembrane adhesive proteins connect inside the cell?
to the cytoskeleton
Where inside the cell do adherens junctions bind?
to cytoskeletal actin
where do desmosomes bind inside the cell?
to intermediate filaments.
Why are cell to cell junctions necessary?
they provide cells and tissues with mechanical support and recruit intracellular signaling molecules to relay positional information to the nucleus
What holds together tight junctions?
occludin and claudin
What do tight junctions do?
form between epithelial cells to regulate transport of particles between cells and preserve polarity by preventing diffusion of membrane proteins between apical and basal regions.
What is ZO1?
marker of tight junctions that indicates neuroepithelial polarity and brain morphogenesis.
What do gap junctions do?
form a pore between adjacent cells allowing small molecules and ions to pass providing metabolic and electrical coupling between cells. (communication)
What is connexins?
gap junction protein
What do adherens junctions do?
hold adjacent cells together.
What are the types of adherens junctions?
zonula adherens junction
autotypic adherens junctions
What are adherens junctions composed of?
cadherins- a cell membrane glycoprotein
How do cadherins work?
they act as a zipper between two cells
What links cadherin to actin filaments?
catenins-zonula adherens adaptor proteins
What shape is the cadherin?
parallel or cis homodimer
What is inside the cell that the cadherin interacts with?
p120 catenin, beta-catenin, and alpha-catenin, vinculin, alpha-actinin and formin-1 FINALLY to actin
What does pac mutation do?
affects cell to cell adhesion in the midbrain-hindbrain region.