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BIO315H5 Study Guide - Midterm Guide: Protein Kinase, Tyrosine, Phosphorylation


Department
Biology
Course Code
BIO315H5
Professor
Feng Chen
Study Guide
Midterm

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BIO 315 Test 1
Enzyme Coupled Cell Receptors
1. Receptor Tyrosine Kinase
2. Tyrosine Kinase Associated Receptors
3. Receptor Serine/Threonine Kinases
4. Histidine Kinase Associated Receptors
5. Receptor Guanylyl Cyclases
6. Receptorlike tyrosine phosphatases
RTK – Receptor Tyrosine Kinases
- many extracellular signals act through Receptor Tyrosine Kinases
- Because these signaling methods have a cytosolic side and extracellular side a
conformational change throught the lipid bilayer would be really diffuclt  like it
is for G protein so - they activated as the ligand binds to the receptor chains to
DIMERIZE bringing the kinase domains of two receptor chains together
(INDUCED PROXIMITY)
- So they can be activated and cross phosphorylate each other on multiple
tryorisnes == Transautophosphorylation
RTK and Signal Complex Formation
Phosphorylation
1. Increase kinase activity of the receptor
2. Creates high affinity docking sites for binding of specific intracellular
signaling proteins
- each signaling protein binds to specific phosphorylated sites on the activated
receptors because it contains a specific phosphotyrosine binding domain that
recongines surroudnign fatures of the polypeptide chain in addition to the
phosphtryosine
- once bound to the RTK a signaling protein may itself become phosphorylated on
tryosines and thereby activated
oBinding itself may be sufficient to activate the docked signaling protein by
either;
Induced conformational change
Bringing it near the protein that is next in the signaling pathway
Proteins with SH2 (Src Homology Region) Domains Bind to Phosphorylated Tyrosines

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- proteins that bind to RTK usually have a conserved phosphotyrosine binding
domain  SH2 Domains
orecognize specific phosphorylated tyrosines  small interaction domains
enable the proteins that contain them to bind to activated RTKs
o*** SH2 wont bind to any, look on diagram it needs to bind beside a
binding site for a amino acid chain (Specific)
SH2 Domain and PDGF Signaling
Key points
- recruitment of signaling proteins are very site specific  require recognition of
neighboring residues
- You have have 5 binding sites but for ex PLC-y will only bind to a specific site
because it has specific residues
oSome proteins are recruited are to relay signal
oSome proteins are recruited can be used for negative feedback
oSome proteins can be used as adapters to recruit other proteins
Mechanisms
Ras: a monomeric GTPase
Ras is a monomeric G-protein (one single subunit). The subunit can bind to GDP
and GTP and has GTPase activity
Ras superfamily consists of manly G-proteins but we will only focus on Ras and
Rhos
Ras is membrane-tethered via a lipid anchor
Two conformational states: GTP-bound (active) vs GDP-bound (inactive)
Ras-GEFs stimulate dissociation of GDP and the subsequent uptake of GTP from
the cytosol  activating Ras
Ras-GAPs increase the rate of hydrolysis of bound GTP by Ras  inactivating Ras
RTKs activate Ras by indirect coupling of the receptor to a Ras-GEF, driving Ras
into an active state
GEF can also serve to bring along other proteins for downstream signaling and
thus serve as a scaffold
Hyper activation of Ras can promote cancer
Ras signaling in Fly Eye Development

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Each unit if the eye is called ommontedia
There are 8 photoreceptors in the eye of the fly.
The development of photoreceptor 7 (R7) depends on RTK signaling.
Mutation in the RTK (seven)  no R7 (sevenless)
R7 can only be activated by a ligand on R8 (Boss)
Activated RTK via binding to Boss phosphorylation of RTKrecruitment of
adaptor protein (one SH2 and two SH3)recruits Ras-GEF (Son of Sevenless-
Sos)GTP exchanged for GDPactive Ras downstream signaling.
Ras can also be activated by GCPR activation by some of its downstream
effectors s/a Ca2+ and DAG.
Ras Signaling
Tyrosine phosphorylations on the RTK and Ras activation are usually short-
lived due to the actions of tyrosine-specific protein phosphatases and GAPs,
respectively.
These signals are converted to longer-lasting signals that may ultimately
impact gene expression THUS USE MAPK
Mitogen-activated protein kinase (MAPK) cascade
Ras-MAPK Signaling Pathway
MAPK is found in all organisms. It is a signaling pathway that uses 3
sequential kinases. The first kinase is called the MAPKKK activates MPKK
activates MPK. The upstream kinase (MPKKK) is activated by Ras and
MPKKK activates MPKK via phosphorylation and MPKK activates MPK via
phosphorylation
MPK can act on a number of different targets (in the cytoplasm, nucleus, some
mediate transient events, some mediate gene expression) via phosphorylation
The kinases are serine/threonine so only phosphorylate at those residues and
when the terminal kinase (MAPK) phosphorylates transcription factors, it can
induce expression of immediate early gene (turned on w/o any new protein
synthesis of its transcription factor)
The duration of MAPK activity varies and dictates what happens in the cell
Duration of MAPK activity is via +/- feedbacks
Ras-MAPK signaling pathway
Duration of MAPK signaling is influenced by positive and negative feedback
loops
oe.g. all-or-none response of frog oocyte maturation requires positive
feedback
Negative feedback can occur through the actions of MAPK- regulated, dual-
specificity protein phosphatases, which subsequently inactivate MAPK.
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