BIO230H1 Lecture Notes - Lecture 5: Receptor Tyrosine Kinase, Sh2 Domain, Histidine Kinase
Lecture Nine: Signaling Via Protein Modifications
Signaling Via Protein Modifications:
1. Enzyme–Coupled Receptors (and protein phosphorylation)
2. Use of Proteolysis in Signaling
Enzyme – Coupled Receptors (and Protein Phosphorylation):
• There are six main classes of enzyme-coupled receptors:
i. Receptor Tyrosine Kinases
ii. Tyrosine-Kinase-Associated Receptors
iii. Receptor Serine/Threonine Kinases
iv. Histidine-Kinase-Associated Receptors
v. Receptor Guanylyl Cyclases
vi. Receptor-like Tyrosine Phosphatases
Receptor Tyrosine Kinases:
• 60 encoded in the human genome
• Mediate essential functions in the body
• Some bind secreted proteins and
others bind to cell surface proteins
• Transmembrane proteins – they have
tyrosine kinase domains (inside the cell)
o Some of them contain kinase
insert region (a couple of amino acids in the middle)
Signaling Molecules Induce the Transautophosphorylation of Receptor Tyrosine Kinase:
• Ligand binding dimerize the receptor
o Signal binds to the inactive RTKs
• Their kinase domains are brought together
and they phosphorylate each other
o Crossphosphorylation occurs at the same time
by activated kinase domains
• Phosphorylation of the kinase domains
enhances their activity
• Phosphorylation of other regions creates docking
sites to assemble a signaling complex
this is a tyrosine kinase hence they phosphorylate each other at tyrosine residues
• Phosphorylated RTK recruit proteins which mediate
downstream signaling (specific proteins bind to specific sites)
o The recruited proteins contain domains (SH2 or PTB
domains) that bind to phosphotyrosine and neighboring
sequences
▪ They have different binding domains which
result in specificity
find more resources at oneclass.com
find more resources at oneclass.com
Examples of Proteins Recruited to Phosphorylated PDGF Receptor:
• There is a signaling molecule that dimerize the RTKs together
• The proteins often contain
additional domains
(Ex. SH3 domains which
bind to proline-rich regions)
• They can function as adaptors
to recruit proteins without SH2 domains
Genetic Studies in the Drosophila Eye:
• Identified core components of the receptor tyrosine kinase signaling pathway
• The drosophila compound eye consists of ~800 ommatidia
• The ommatidia are composed of 8 photoreceptor cells and 12 support cells
• They arise from a simple epithelial sheet through the sequential differentiation of the
photoreceptor cells
i. R8 is the initial cell, and it will
differentiate and will tell
its neighboring cells to differentiate into R2 and R5
ii. R8 will tell its neighboring cells to differentiate into R3 and R4
iii. R8 will tell its neighboring cells to differentiate into R1 and R6
iv. Finally, the last cell that differentiates is R7
o The R7 photoreceptor cell is needed to detect UV light
▪ Flies without an R7 photoreceptor cell will fail to see in UV light
a) Sevenless (Sev)
o The normal Sevenless protein was shown to be a receptor tyrosine
kinase expressed in R7 cells (must dimerize and have transautophosphorylation)
o The protein Sevenless is required or else R7 will be missing
b) Bride-of-Sevenless (Boss)
o The normal Bride-of-Sevenless protein
was shown to be the ligand for Sevenless
expressed on R8 cells
o The R8 cell requires Boss to activate
Sevenless (in the R7 cell) to get the
neighboring cell to change to R7
c) Drk (Downstream of Receptor Kinase)
o Links Sev to SOS
▪ Has an SH2 domain which recognizes the phosphotyrosine on Sev
▪ Has an SH3 domain which recognizes the proline rich sequences on SOS
o Also activates SOS
d) Son-of-Sevenless (SOS)
o When SOS is activated it acts as an GEF for Ras
o This allows the activation of Ras and signals downstream
find more resources at oneclass.com
find more resources at oneclass.com
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BIO230H1 Full Course Notes
Verified Note
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Document Summary
Signaling via protein modifications: enzyme coupled receptors (and protein phosphorylation, use of proteolysis in signaling. Enzyme coupled receptors (and protein phosphorylation): there are six main classes of enzyme-coupled receptors, receptor tyrosine kinases, tyrosine-kinase-associated receptors, receptor serine/threonine kinases, histidine-kinase-associated receptors, receptor guanylyl cyclases, receptor-like tyrosine phosphatases. Examples of proteins recruited to phosphorylated pdgf receptor: there is a signaling molecule that dimerize the rtks together, the proteins often contain additional domains (ex. Sh3 domains which bind to proline-rich regions: they can function as adaptors to recruit proteins without sh2 domains. Its activity leads to cell proliferation or differentiation. Ras activation: ras activates a mitogen-activated protein kinase module (map kinase module) to change protein activity and gene expression, when ras is activated it will activate. Map kinase modules, insulating them from other modules which increases response specificity: different arrangements of the. Map kinases" can lead to different cell responses (ex.
